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Review

Proteolytic Landscapes in Gastric Pathology and Cancerogenesis

by
Sabine Bernegger
1,
Miroslaw Jarzab
1,
Silja Wessler
1,2 and
Gernot Posselt
1,*
1
Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria
2
Cancer Cluster Salzburg and Allergy Cancer BioNano Research Centre, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(5), 2419; https://doi.org/10.3390/ijms23052419
Submission received: 5 January 2022 / Revised: 17 February 2022 / Accepted: 18 February 2022 / Published: 22 February 2022
(This article belongs to the Special Issue Homeostasis and Cancer Initiation: New Insights into the Gastric Mucosa)
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Abstract

:
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.

1. Introduction

Cancer is a leading cause of premature death in 127 countries, and if current numbers and trends continue, cancer could overtake cardiovascular disease in this century [1]. Among all common cancer types, stomach cancer accounted for 5.6% of all new cancer cases and 7.7% of cancer-related deaths in 2020 [2]. Gastric cancer appears as two pathological variants. The diffuse type is characterized by the development of linitis plastica and is associated with an unfavorable prognosis due to a heritable loss-of-function mutation of the E-cadherin gene CDH1. The intestinal type of gastric cancer is mainly considered as an infectious disease, since persistent colonization with the human pathogen Helicobacter pylori (H. pylori) has been discovered as the main cause. Although erosive gastritis can be caused by stress, alcohol, or chemical drugs, up to 89% of non-cardia gastric cancers are attributable to H. pylori infection [3]. Several infections are associated with cancer development, however, it was estimated that out of 2.2 million infection-attributed cancer cases diagnosed worldwide, H. pylori was the primary cause of 810,000 cases in 2018 [4].
A major problem in gastric cancer therapy is late diagnosis, as the early stages of gastric cancer are usually clinically asymptomatic. H. pylori-mediated, inflammation-driven gastric cancer development is a multistep process taking decades and is described as the “Correa cascade”. It is characterized by a prolonged precancerous process with well-defined sequential stages initiated by chronic active gastritis, chronic atrophic gastritis, intestinal metaplasia, and dysplasia, which can finally result in invasive carcinoma [5,6]. Intensive research has revealed a large set of different pathogenic factors originated from H. pylori that induce a complex network of molecular and cellular mechanisms leading to H. pylori-mediated inflammatory responses, and subsequently, carcinogenesis, which have been summarized recently in excellent review articles [7,8,9,10].
Awareness of the importance of proteases in gastric cancer has increased in recent years. Different types of proteases, including a number of (matrix) metalloproteases, serine proteases, collagenases, and so on, derived from either the epithelium, the immune cell infiltrate, or H. pylori are involved in numerous pathogenesis-associated signaling pathways. They contribute to the release of signaling molecules, cleavage of cell surface proteins, and modulation of the extracellular matrix to ensure successful colonization of the gastric epithelium and foster subsequent pathologic events [11,12]. These processes involve the immediate early pro-inflammatory response, the loss of the epithelial integrity, or the induction of the epithelial-mesenchymal transition (EMT) and cancerogenesis in the polarized epithelium.

2. The Role of Proteases in H. pylori Colonization and Mucosal Inflammation

A high percentage of gastric adenocarcinomas (GACs) are linked to H. pylori infection or autoimmune gastritis, and thus GAC is considered a paradigm of inflammation-driven carcinogenesis [13,14,15]. Although the pathogenicity of intestinal-type and diffuse-type carcinoma differs also in their correlation with H. pylori colonization [16], both are associated with genetic predispositions in a number of inflammatory mediators [17].
The importance of bacterial and host proteases for a successful epithelial colonization by H. pylori has been investigated in a number of studies. The epithelial lining of the stomach is covered by a thick mucus layer, which facilitates transport of chyme and provides protection of the stomach tissue against chemicals and pathogens. Despite initial studies reporting the existence of an unknown H. pylori protease that softens mucus and supports colonization, no definite mucinase has yet been identified in H. pylori [18,19]. However, motility through the dense mucus layer is accomplished by altering the viscoelastic properties via pH and urease-dependent mechanisms [20]. Amongst H. pylori proteases, the expression and secretion of the collagenase Hp0169 was shown to be a prerequisite for bacterial colonization in vivo [21]. Hp0169 was described to act as a true collagenase able to degrade native triple-helical type I collagen in the ECM and facilitate bacterial adherence [21]. A significant role of the collagen and extracellular matrix in bacterial colonization is supported by the fact that host proteases of the matrix-metalloproteinase (MMP) family targeting collagen, such as MMP7 and MMP10, also affect H. pylori colonization levels (Figure 1). A number of MMPs are upregulated and activated during H. pylori gastritis and gastric cancer (cf. Section 4 and Section 5). Interestingly, MMP10 supports colonization, whereas MMP7 levels are inversely correlated with bacterial burden [22,23]. The opposite effect of these host proteases could be linked to their association with the host immune response and inflammation, rather than to their direct proteolytic activity in the tissue. Levels of infiltrating B cells and T cells, and in particular Th1- and Th17-associated cytokines like interferon gamma (Ifn-γ) and interleukin-17 (IL-17), are elevated in MMP7 knockout mice [24]. On the other hand, in concert with IL-22, MMP10 fosters CD8+ T-cell-mediated tissue inflammation, which aids H. pylori survival, and deletion of MMP10 is associated with reduced tissue colonization [23].
In particular, ECM-targeting proteases are important determinants shaping the micromilieu and support the establishment of persistent H. pylori infections in a controlled pro-inflammatory environment. Epithelial colonization with H. pylori has a strong impact on the local tissue microenvironment [25]. In addition to the local inflammatory response in the epithelium, epithelial mediators attract a massive immune cells infiltrate. Immigrating neutrophils, macrophages, and lymphocytes drastically change the cellular composition of the gastric mucosa [26,27]. In many cases, the literature does not identify the origin of the individual factors that form the microenvironment, and it remains unclear whether the factors are produced by the inflamed tissue, the newly recruited immune cell infiltrate, or both. Despite particular ambiguities in the producing source, a clear increase in proteolytically active (metallo-)protease levels is seen in the inflammatory microenvironment in the gastric mucosa (Table 1). A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), -17, and -19 are upregulated in H. pylori-infected individuals, and ADAM9, -12, -15, and -20 are deregulated in cancer biopsies [28,29,30]. Similarly, a variety of MMPs are upregulated in vivo in H. pylori gastritis (MMP1, -8, -9, and -10) and in malignantly transformed tissue (MMP2, -7, -9, -11, -12, -14) [31,32,33,34,35,36,37]. In vitro infection experiments with gastric cancer cell lines support a direct regulation of MMP1, -3, -7, -8, -9, and -10 in the epithelium in response to H. pylori infection [34,38,39]. The impact of the proteolytic activities in the inflamed mucosa on the inflammatory tissue microenvironment is twofold. First, direct effects on inflammatory mediators and cytokines are seen. ProTNF-α is canonically processed and shed from producing cells in an ADAM17-dependent manner [40,41], but MMP1 and MMP7 have also been suggested as potential TNF-α sheddases [42,43]. ADAM17 also contributes to proTGF-α processing in H. pylori infections [44], whereas MMP1 is involved in cleaving proIL-1β [42]. Other studies indicate that MMP7 dampens the production of the cytokines IL-1β, MIP-1β, TNF-α, IP-10, RANTES, and IL-17, as MMP7-deficient mice produced higher levels as compared to wild-type animals [22]. This is in line with studies reporting overshooting inflammation in MMP7 knockout animals and thus suggest a protective role of MMP7 in vivo [24]. Not only are cytokines affected by proteolytic processing, but the chemoattractant potency of chemokines is also subject to modification by targeted cleavage events. It has been demonstrated that CXCL5 and CXCL8 potency can be amplified in a gelatinase (i.e., MMP2 and -9)-dependent manner and results in boosted neutrophil recruiting, whilst other chemokines such as CXCL1 are inactivated by cleavage [45,46]. A pronounced effect of the MMP10-CXCL16 axis was also observed on the recruitment of a CD8+ T cell infiltrate [23]. Therefore, the proteolytic constituents in the tissue microenvironment are influencing the inflammatory and chemo-attractive properties at the site of inflammation [47]. In return, the resulting tissue microenvironment governs protease production. For instance, the gelatinases MMP2 and -9 are upregulated in a Th17 environment via IL-21 [48,49] and tissue levels of IL-1β are closely linked to MMP3 expression in vivo [50]. MMP7 production depends on gastrin [51], which is considered an important mediator of gastric tumorigenesis [52]. In addition to cytokines and chemokines, growth factor activity also is subject to regulation via protease-dependent mechanisms. HB-EGF (heparin-binding EGF-like growth factor) shedding is observed in response to ADAM17 activation [53], and MMP7 was also suggested as a HB-EGF sheddase [54]. HB-EGF as well as TGF-α activity results in epidermal growth factor receptor signaling, which is associated with a local stimulation of cell proliferation [44,55]. Second, proteases target the extracellular matrix in the inflamed tissue and thus aid the recruitment of an immune cell infiltrate, which supports inflammation and contributes to pathogenic tissue remodeling. Most prominently, the gelatinase MMP9 is correlated with tissue-infiltrating macrophages [56]. The concerted action of proteases derived from the epithelium, infiltrating and activated immune cells, as well as H. pylori proteases foster disease progression. MMP-dependent ECM remodeling is not only linked to inflammation but also directly contributes to gastric ulceration [57,58]. Besides the abovementioned host proteases, the H. pylori protease high temperature requirement A (HtrA) was suggested to contribute to chronic inflammation, as the leucine 171 variant of HtrA was associated with higher inflammation scores and elevated serum gastrin levels [59]. The authors speculate that altered HtrA activity in the S171L HtrA variant could potentially mediate more efficient migration over the epithelial barrier and thus influence inflammation and gastrin production [59]. HtrA was originally discovered as a periplasmic serine protease and chaperone with essential functions in H. pylori growth and survival [60,61,62]. As a secreted protease, HtrA exerts important functions in the disintegration of the gastric epithelium via targeting epithelial junctions (cf. Section 3).
Acute H. pylori infection induces hypochlorhydria, which facilitates the colonization by the bacteria. In chronic infections, corpus-predominant colonization and pan-gastritis results in acid hypo-secretion, whilst antrum-predominant gastritis is often associated with acid hyper-secretion [87,88]. The reduction in acid production in H. pylori infections was at least partly attributed to an ADAM17-dependent transcriptional repression of the gastric H, K–adenosine triphosphatase α-subunit [63].

3. Proteolytic Impairment of Junctional Integrity and Epithelial Barrier Function

The gastric mucosal epithelium represents one of the main contact areas with the outside world and provides an effective protective barrier, which is characterized by a high order of 3D organization and cellular polarization. It features numerous glands and pits and a defined distribution of the various cell types specialized in fulfilling these complex requirements. Besides mucus-secreting cells, specialized cells such as parietal cells, chief cells, and entero-endocrine cells mediate the production of gastric acid, the production and secretion of digestive and antimicrobial enzymes, and hormones, respectively [89,90,91]. A prerequisite for the integrity and maintenance of the gastric epithelial barrier is the maintenance of cell polarity facilitated by several adhesive cell–cell connections, including tight junctions (TJ), adherens junctions (AJ), and desmosomes [92] (Figure 1). Structurally, these junctions consist of transmembrane proteins as central key molecules that mediate the intercellular adhesion and form intracellular protein complexes to stabilize the junctions and link them to the actin cytoskeleton. They control several important signal transduction pathways involved in inflammation and carcinogenesis [93,94,95,96,97].
In healthy individuals, the maintenance of a functional epithelial barrier requires a continuous cell turnover accompanied by homeostatic changes in intercellular junction proteins [98]. In recent years, it became evident that proteolytic impairment of barrier functions is strongly linked to the disease progression in gastric cancer pathogenesis. This has been demonstrated for deregulated host proteases and proteases expressed by pathogenic bacteria such as H. pylori.
TJs are crucial for maintaining apical-basolateral cell polarity and are responsible for the regulation of paracellular permeability. TJs are a network of proteins at the lateral cell surface of epithelial cells, including claudins, occludin, the junctional adhesion molecule-A (JAM-A), and intracellular scaffold proteins, such as zonula occludens (ZO) and tricellulin [99]. Recently, it has been shown that the four-span transmembrane TJ proteins occludin and claudin-8 are cleaved in an extracellular loop during infection of gastric epithelial cells with H. pylori. Cleavage of the two TJ proteins was attributed to the secreted bacterial serine protease HtrA [81]. Cleavage of occludin and members of the claudin protein family can also occur through upregulation of host proteases, such as MMP2, MMP7, and MMP9, and is usually associated with an increase in epithelial or endothelial permeability [70,74,100,101,102,103]. Although these proteases were shown to be induced in response to H. pylori infection [39,65] and in gastric cancer tissue [104,105], a direct role of these proteases in disruption of the gastric epithelium has not been established so far. Recently, JAM-A has been described as a target of H. pylori, and Hp1012 was suggested as the responsible protease. Although JAM-A is cleaved in response to H. pylori infection and by a protein fraction also containing Hp1012, direct cleavage of JAM-A by the recombinant protein was not shown. Nevertheless, the observed cleavage event in the intracellular JAM-A c-terminus results in impaired barrier function, reduced intercellular adhesion, and increased invasive potential of epithelial cells [78].
Beneath the TJs, AJs are located, in which the tumor suppressor E-cadherin represents the adhesive core component. E-cadherin is a glycosylated transmembrane protein with five extracellular cadherin-motifs, a single-pass transmembrane segment, and a short conserved cytoplasmic domain, which interacts with β-catenin, plakoglobin (γ-catenin), and p120-catenin. β-catenin also interacts with α-catenin that is linked to filamentous actin. β-catenin is a proto-oncogene as it plays an important role in the Wnt signaling pathway. Both β-catenin and p120-catenin exhibit a second role in the nucleus, where they control transcription factors like Tcf/lef and Kaiso, which regulate the expression of cancer-associated target genes, such as c-myc, cyclin D1, mmp7, and so on [106,107]. In normal epithelial cells, E-cadherin is constantly shed at a low rate from the cell surface, in the process of dynamic control of intercellular adhesions. However, aberrant ectodomain shedding of E-cadherin was reported in various types of cancer and has been suggested as a prognostic marker in gastric cancer [108,109]. Numerous soluble and membrane-anchored host proteases have been associated with E-cadherin shedding, such as the matrix metalloproteases MMP3, MMP7, MMP9, MMP14 [71,73,75,77], ADAM10, and ADAM15 [68,110], which are upregulated in response to H. pylori infection [38,39,65,66,111] and in gastric cancer tissue [104,105]. In addition to the induction of host proteases, H. pylori also exerts direct effects on E-cadherin shedding mediated by the HtrA protease that cleaves E-cadherin on infected gastric epithelial cells [79]. Apart from ectodomain shedding of E-cadherin, intracellular cleavage events in E-cadherin were also shown to severely impair epithelial integrity. In the context of H. pylori infections, upregulation of calpain and caspase-3 induced intracellular E-cadherin cleavage, resulting in disintegration of the E-cadherin/catenin complex and increased apoptosis of gastric epithelial cells [82,83,85].
Desmosomes represent the third major intercellular adhesion complex, and are located beneath AJ in the polarized epithelium. In the gastric mucosa, the desmosomal cadherins desmoglein-2 and desmocollin-2 represent the adhesive core components of desmosomes [112]. Although downregulation of desmoglein-2 has been associated with gastric cancer [113], not much is known about abnormal proteolytic cleavage of desmosomal cadherins in the context of gastric cancer progression. Recently, H. pylori HtrA was shown to directly cleave desmoglein-2 in the extracellular domain on gastric epithelial cells, thereby inducing a soluble desmoglein-2 fragment [80]. A similar fragment was associated with a compromised mucosal barrier function linked to matrix metalloproteases in settings of intestinal inflammation [114,115]. Moreover, enhanced desmoglein-2 shedding was associated with induction of MMPs, as well as ADAM9, ADAM15, and ADAM17, and impaired cell adhesiveness in squamous cell carcinoma [69,76]. Although no direct experimental evidence proves the impact of these proteases on desmosomes in gastric cancer, similar mechanisms appear plausible due to the documented expression of these proteases in response to H. pylori infection [30,116] and in gastric cancer [104,117].
Like the targeting of E-cadherin, intracellular cleavage of desmoglein-2 by caspases or calpain has been associated with induction of apoptosis in the inflamed intestinal epithelium [84,86]. Again, despite the lack of experimental data, it might be speculated that increased activation of caspase-3 and calpain by H. pylori could enhance intracellular desmoglein-2 cleavage and thus stimulate apoptosis in gastric epithelial cells.
Cleavage of TJ proteins, E-cadherin, and desmosome proteins locally opens intercellular adhesions and thus allows transmigration of H. pylori to the basolateral and basal domains of the polarized gastric epithelium [79,81]. Overcoming the epithelial barrier and gaining access to basolateral integrin-β1 for the delivery of the bacterial oncoprotein cytotoxin-associated gene A (CagA) is an integral disease mechanism in H. pylori-dependent carcinogenesis [118]. Although ADAM10 is activated in H. pylori-infected cells and cleaves E-cadherin [66], HtrA is the main E-cadherin protease in H. pylori infections [79,80].
Taken together, abnormal cleavage of junction proteins severely impairs the barrier properties of the gastric epithelium. On the one hand, reduction of functional cell–cell junction complexes reduces intercellular adhesion, which is usually associated with increased aggressiveness and invasiveness of carcinoma as it increases the migration and invasive potential of epithelial cells [119,120]. In particular, loss of E-cadherin is a characteristic step in epithelial-mesenchymal transition and, in the context of tumor progression, often plays a causative role in malignant transformation [121] (cf. Section 5).

4. The Role of Proteases in Proliferation, Cell Survival, and Neoplastic Transformation

Proteolytic activities feed into proliferative and anti-apoptotic signaling pathways and influence cell differentiation [122], and causal links between proteases and tumorigenic cell transformation have even been drawn (Figure 2) [123]. However, the mutational burden in gastric cancer does not point to specific protease-activated processes [124]. Nevertheless, a tumor-promoting role for ADAM and MMP proteins is clearly established in many cancer types, and their expression levels could serve as a prognostic marker in cancer (Table 2) [125]. In gastric cancer, MMP2, -3, -7, -9, -10, and -11 are upregulated in the course of disease progression, of which MMP2, -3, -7, and -9 have been suggested to have prognostic value for disease outcome [31,36,59,126,127,128,129,130,131]. MMP7 was shown to promote proliferation in non-transformed epithelial cells [132]. A meta-analysis revealed ADAM17 as a significant biomarker for poor prognosis in gastric cancer [133]. In contrast, beneficial effects of MMP12 expression have been discussed and expression levels were suggested to correlate inversely with disease outcome [37,134]. MMP11 levels also correlate with IGF-1 expression and IGF-1-stimulated proliferation [36,42]. Antibody-mediated inhibition of ADAM9 and -15 reduced in vitro proliferation of gastric cancer cell lines, whereas anti-ADAM12-treated cells produced higher proliferation rates [117]. ADAM17 induces pro-survival signaling via the EGFR signaling axis and protects from H. pylori-induced apoptosis. In this context, EGFR kinase inhibitors could extenuate premalignant pathology in gerbil models [44,135,136]. Additionally, the shedding and release of TNF-α via ADAM17 and several MMPs changes the balance between cell survival and apoptosis. [137]. Nevertheless the interrelation of MMPs and cell survival is ambiguous, and the same MMPs can exhibit both pro-apoptotic and anti-apoptotic activity [138].
Anti-apoptotic function of MMPs can be executed by cleaving the Fas ligand, shedding of tumor associated MHC complex class I-related protein, or activation of AKT/Protein kinase B. The pro-apoptotic activity of MMPs is often connected to changes in ECM composition and cleavage of adhesion molecules [64]. H. pylori infection itself also interferes with pro- and anti-apoptotic pathways. For instance, H. pylori TieA protein induced gastric epithelial cell death via Fas- and caspase-8-mediated apoptosis [143]. Nevertheless, H. pylori utilizes numerous strategies to reduce caspase-3-dependent apoptosis in infected host cells, like the induction of anti-apoptotic proteins of the cIAP family [141,142]. On the other hand, H. pylori LPS-stimulated MMP9 was shown to induce pro-apoptotic cleaved caspase 3 and reduced cell survival [140].
In addition to the observed anti-apoptotic effects and the stimulation of cell proliferation, proteases like ADAM17 and ADAM10 imprint a cancer stem cell phenotype in cells by shedding of Notch1, and thus support anchorage-independent growth [67]. Interestingly, a variant of H. pylori HtrA displaying a leucine residue at position 171 was also enriched in gastric cancer patients as compared to patients with non-ulcer dyspepsia and peptic ulcers. It can be speculated that a higher efficiency in basolateral CagA delivery by H. pylori is linked to a higher risk for developing gastric cancer [59].

5. Disease Progression in a Proteolytic Environment: Epithelial-Mesenchymal Transition, Metastasis, and Neo-Angiogenesis

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells lose the expression of epithelial traits and gain the expression of mesenchymal marker proteins. A characteristic of EMT is the loss of epithelial marker proteins (E-cadherin, catenins, etc.) expression either via transcriptional regulation, delocalization, or proteolytic degradation. In turn, the decreased E cadherin expression results in deregulated β-catenin signaling and the stabilization of the mesenchymal phenotype via transcription factors of the SNAIL, TWIST, and ZEB families [165]. H. pylori infection was suggested to induce an EMT-like phenotype in a number of studies (recently reviewed in [166]), and E-cadherin expression is frequently lost in premalignant metaplasia and early stages of gastric cancer [167], while only a smaller fraction of gastric cancer samples expressed the mesenchymal marker protein N-cadherin [168].
In fact, the proteolytic shedding of E-cadherin might contribute to the loss in epithelial stability and cell identity well before the transcriptional down-regulation during EMT [169]. The formation of soluble E-cadherin fragments shows a strong oncogenic potential, as these fragments can directly bind and activate receptor tyrosine kinases. Thereby, enhanced E-cadherin shedding is involved in induction of pro-oncogenic signaling pathways, such as the PI3K-Akt-mTor pathway or the MAPK-Erk pathway, and results in tumor cell growth, survival, and motility [68,170,171,172,173]. H. pylori infection also leads to the formation of two intracellular E-cadherin fragments, which are released into the cytosol [79]. Consequently, the intracellularly complexed β-catenin and p120-catenin are also released from the complex [174]. Translocation of β-catenin and p120-catenin have been observed in H. pylori-infected gastric epithelial cells as well. Once released from the E-cadherin complex, β-catenin binds the Tcf/lef transcription factors in the nucleus and enhances the transcriptional activity [175]. This effect is supported by nuclear p120-catenin binding the transcriptional repressor of Kaiso to relieve suppressed MMP7 expression [176].
EMT processes in gastric cancer are invariably associated with an inflammatory tissue microenvironment, and both factors synergize in unfolding the metastatic potential of transformed cells (Figure 2) [177]. Importantly, several proteases, which are frequently found in the gastritis- and gastric-cancer-associated tissue micromilieu, have been reported to foster EMT processes via several pathways. ADAM10 contributes the shedding of E-cadherin and c-Met [66]. Whilst E-cadherin cleavage clearly feeds into the mesenchymal transition [144], the loss of c-Met expression impairs HGF reactivity of the cells and thus reduces the malignant potential [178]. However, several studies suggest that H. pylori stimulates c-Met-associated pro-oncogenic signaling cascades [145,146]. In gastric cancer cell lines, EMT was critically dependent on ADAM17, and knockdown of ADAM17 was able to reverse EMT transition by abrogating signaling via the TGF-β/Smad axis [147]. Besides TGF-β signaling, the insulin-like growth factor (IGF) signal transduction cascade is crucially involved in EMT in gastric cancer [165,179], where MMP11 knockdown was able to diminish IGF1 signaling and concomitantly reduced the invasive potential of gastric cancer cells [160,161]. In vitro experiments using mammary epithelial cells showed that MMP3 exposure was sufficient to induce SNAIL-dependent EMT [72]. Further, MMP3 is an important effector molecule in the induction of WNT-induced β-catenin signaling during EMT [153]. Therefore, MMP3 has been suggested as a natural tumor-promoting factor [180]. In parallel to the disintegration of cell–cell junctions, cell–ECM interactions are also destabilized by proteases allowing invasive migration of transformed cells [72]. MMP7-dependent HB-EGF signaling was shown to reinforce EMT marker expression [51], and MMP7 inhibition decelerated migration and inhibited the invasive capacity of AGS cells [65]. The importance of ECM targeting enzymes for invasive growth and metastatic cell migration is highlighted by the fact that many of the matrix-targeting MMPs are critically involved in these processes [148]. The gelatinases MMP2 and -9 are crucial in invasion and metastasis and in several tumor entities [134], and the MMP9 promoter allele Rs3918242 is associated with a higher risk of metastasis in gastric cancer [158]. The migration of gastric tumor cell lines was also linked to MMP3, MMP9, and MMP10, which facilitated cell migration over a Matrigel layer, an in vitro model for invasiveness of transformed cells [38,154,155]. The membrane-type metalloproteinase MMP14 fosters migration and invasion in vitro, while in vivo MMP14 expression levels positively correlate with lymph node metastasis [163,164].
As pointed out previously, the tumor microenvironment in general, and in particular, the abundance of proteolytic enzymes is strongly influenced by other cell types, such as infiltrating immune cells or cancer-associated fibroblasts (CAFs). CAF-derived MMP3, secreted by tumor-associated myo-fibroblasts, is sufficient to promote AGS cell migration [152]. Similar observations have been made for MMP10 secreted by tumor-associated macrophages (TAMs) [159]. In a recent study, TAM-derived MMP9 was shown to support metastasis, and treatment with MMP9 inhibitors could reduce distant metastasis in gastric cancer [156]. Little is known about the direct involvement of proteases in angiogenic processes during gastric cancer progression. Remodeling of the ECM is a prerequisite for angiogenesis and self-evidently, MMPs are highly important in this step [181]. Additionally, MMP2 and MMP9 promote angiogenesis via stimulation of V-EGF [149,150,157] and activation of TGF-β signaling [151]. On the other hand, MMP12 activates angiostatin, which is a cleavage product of plasminogen and counteracts angiogenesis [162]. However, the association of MMP12 expression with higher survival rates in gastric cancer patients is controversial [37,182,183].

6. Concluding Remarks

H. pylori-driven gastric pathologies and gastric cancer are closely linked to inflammatory processes and proteolytic reshaping of the tissue microenvironment. The consequences of proteolytic enzymes derived from bacteria as well as host cells affect every level of the Correa cascade outlined above, and thus they can be considered significant contributors to gastric tumorigenesis. Proteases affect tissue architecture and ECM composition, they aid inflammatory processes and immune cell recruitment, and last but definitely not least, they directly target signaling cascades with well-established roles in cancer formation and progression. The variety of proteases involved and the diversity of protease substrates draws a complicated picture of interdependent disease mechanisms. The advent of organoid-based models and stomach-on-a-chip technologies might help to clarify the proteolytic contribution of the individual cells types present in the mucosal microenvironment of the stomach [139]. Nevertheless, targeting individual proteases could provide us with alternative strategies to fight H. pylori-associated disease and gastric cancer. In particular, proteases that contribute to late events in gastric cancer progression, such as metastasis and angiogenesis, might represent attractive targets for therapeutic intervention.

Author Contributions

Conceptualization, S.W. and G.P.; writing—original draft preparation, S.B., M.J., S.W. and G.P.; writing—review and editing, S.W. and G.P.; visualization, S.B.; funding acquisition, S.W. All authors have read and agreed to the published version of the manuscript.

Funding

The work of S.W. was supported by the grants I_4360 and P_31507 from the Austrian Science Fund (FWF). Open Access Funding by the Austrian Science Fund (FWF).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bray, F.; Msc, M.L.; Weiderpass, E.; Soerjomataram, I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer 2021, 127, 3029–3030. [Google Scholar] [CrossRef] [PubMed]
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  3. Plummer, M.; Franceschi, S.; Vignat, J.; Forman, D.; De Martel, C. Global burden of gastric cancer attributable to Helicobacter pylori. Int. J. Cancer 2014, 136, 487–490. [Google Scholar] [CrossRef] [PubMed]
  4. de Martel, C.; Georges, D.; Bray, F.; Ferlay, J.; Clifford, G.M. Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis. Lancet Glob. Health 2020, 8, e180–e190. [Google Scholar] [CrossRef] [Green Version]
  5. Correa, P. Helicobacter pylori and gastric carcinogenesis. Am. J. Surg. Pathol. 1995, 19, S37–S43. [Google Scholar]
  6. Correa, P. Gastric Cancer. Gastroenterol. Clin. N. Am. 2013, 42, 211–217. [Google Scholar] [CrossRef] [Green Version]
  7. Takahashi-Kanemitsu, A.; Knight, C.T.; Hatakeyama, M. Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell. Mol. Immunol. 2019, 17, 50–63. [Google Scholar] [CrossRef] [Green Version]
  8. Wroblewski, L.E., Jr.; Peek, R.M. Helicobacter pylori, Cancer, and the Gastric Microbiota. Adv. Exp. Med. Biol. 2016, 908, 393–408. [Google Scholar] [CrossRef]
  9. Naumann, M.; Sokolova, O.; Tegtmeyer, N.; Backert, S. Helicobacter pylori: A Paradigm Pathogen for Subverting Host Cell Signal Transmission. Trends Microbiol. 2017, 25, 316–328. [Google Scholar] [CrossRef]
  10. Blaser, N.; Backert, S.; Pachathundikandi, S.K. Immune Cell Signaling by Helicobacter pylori: Impact on Gastric Pathology. Adv. Exp. Med. Biol. 2019, 1149, 77–106. [Google Scholar] [CrossRef]
  11. Posselt, G.; Crabtree, J.E.; Wessler, S. Proteolysis in Helicobacter pylori-Induced Gastric Cancer. Toxins 2017, 9, 134. [Google Scholar] [CrossRef]
  12. Sampieri, C.L. Helicobacter pylori and Gastritis: The Role of Extracellular Matrix Metalloproteases, Their Inhibitors, and the Disintegrins and Metalloproteases—A Systematic Literature Review. Am. J. Dig. Dis. 2013, 58, 2777–2783. [Google Scholar] [CrossRef] [PubMed]
  13. Bockerstett, K.A.; DiPaolo, R.J. Regulation of Gastric Carcinogenesis by Inflammatory Cytokines. Cell. Mol. Gastroenterol. Hepatol. 2017, 4, 47–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Toh, B.-H. Diagnosis and classification of autoimmune gastritis. Autoimmun. Rev. 2014, 13, 459–462. [Google Scholar] [CrossRef] [PubMed]
  15. Bizzaro, N.; Antico, A.; Villalta, D. Autoimmunity and Gastric Cancer. Int. J. Mol. Sci. 2018, 19, 377. [Google Scholar] [CrossRef] [Green Version]
  16. Assumpção, P.P.; Barra, W.F.; Ishak, G.; Coelho, L.G.V.; Coimbra, F.J.F.; Freitas, H.C.; Dias-Neto, E.; Camargo, M.C.; Szklo, M. The diffuse-type gastric cancer epidemiology enigma. BMC Gastroenterol. 2020, 20, 1–7. [Google Scholar] [CrossRef] [PubMed]
  17. El-Omar, E.M.; Rabkin, C.S.; Gammon, M.D.; Vaughan, T.L.; Risch, H.A.; Schoenberg, J.B.; Stanford, J.L.; Mayne, S.T.; Goedert, J.; Blot, W.J.; et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003, 124, 1193–1201. [Google Scholar] [CrossRef]
  18. Suerbaum, S.; Friedrich, S. MicroCorrespondence. Mol. Microbiol. 1996, 20, 1113–1114. [Google Scholar] [CrossRef]
  19. Smith, A.W.; Chahal, B.; French, G.L. The human gastric pathogen Helicobacter pylori has a gene encoding an enzyme first classified as a mucinase in Vibrio cholerae. Mol. Microbiol. 1994, 13, 153–160. [Google Scholar] [CrossRef]
  20. Ebansil, R.; Celli, J.P.; Hardcastle, J.M.; Turner, B.S. The Influence of Mucus Microstructure and Rheology in Helicobacter pylori Infection. Front. Immunol. 2013, 4, 310. [Google Scholar] [CrossRef] [Green Version]
  21. Kavermann, H.; Burns, B.; Angermüller, K.; Odenbreit, S.; Fischer, W.; Melchers, K.; Haas, R. Identification and Characterization of Helicobacter pylori Genes Essential for Gastric Colonization. J. Exp. Med. 2003, 197, 813–822. [Google Scholar] [CrossRef] [PubMed]
  22. Krakowiak, M.S.; Noto, J.M.; Piazuelo, M.B.; Hardbower, D.M.; Romero-Gallo, J.; Delgado, A.; Chaturvedi, R.; Correa, P.; Wilson, K.T.; Peek, R.M. Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization. Oncogene 2014, 34, 1865–1871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Lv, Y.-P.; Cheng, P.; Zhang, J.-Y.; Mao, F.-Y.; Teng, Y.-S.; Liu, Y.-G.; Kong, H.; Wu, X.-L.; Hao, C.-J.; Han, B.; et al. Helicobacter pylori–induced matrix metallopeptidase-10 promotes gastric bacterial colonization and gastritis. Sci. Adv. 2019, 5, eaau6547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Ogden, S.R.; Noto, J.M.; Allen, S.S.; Patel, D.A.; Romero-Gallo, J.; Washington, M.K.; Fingleton, B.; Israel, D.A.; Lewis, N.; Wilson, K.; et al. Matrix Metalloproteinase-7 and Premalignant Host Responses in Helicobacter pylori–Infected Mice. Cancer Res. 2010, 70, 30–35. [Google Scholar] [CrossRef] [Green Version]
  25. Salim, D.K.; Sahin, M.; Köksoy, S.; Adanir, H.; Süleymanlar, I. Local Immune Response in Helicobacter pylori Infection. Medicine 2016, 95, e3713. [Google Scholar] [CrossRef]
  26. Tsai, H.-F.; Hsu, P.-N. Interplay between Helicobacter pylori and immune cells in immune pathogenesis of gastric inflammation and mucosal pathology. Cell. Mol. Immunol. 2010, 7, 255–259. [Google Scholar] [CrossRef] [Green Version]
  27. Algood, H.M.S.; Gallo-Romero, J.; Wilson, K.T.; Peek, R.M., Jr.; Cover, T.L. Host response to Helicobacter pylori infection before initiation of the adaptive immune response. FEMS Immunol. Med. Microbiol. 2007, 51, 577–586. [Google Scholar] [CrossRef] [Green Version]
  28. Clark, I.M.; Swingler, T.E.; Sampieri, C.L.; Edwards, D. The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol. 2008, 40, 1362–1378. [Google Scholar] [CrossRef] [Green Version]
  29. Thomas Wex, A.S.-M.; Kalinski, T.; Roessner, A.; Malfertheiner, P.; Naumann, M.; Lendeckel, U. Expression of Adam 19 in Helicobacter pylori-Mediated Diseases and Gastric Cancer; Gastric Cancer Research Trends; Nova Science Publishers: New York, NY, USA, 2007; p. 171. [Google Scholar]
  30. Yoshimura, T.; Tomita, T.; Dixon, M.F.; Axon, A.T.R.; Robinson, P.A.; Crabtree, J.E. ADAMs(A Disintegrin and Metalloproteinase) Messenger RNA Expression in Helicobacter pylori–infected, Normal, and Neoplastic Gastric Mucosa. J. Infect. Dis. 2002, 185, 332–340. [Google Scholar] [CrossRef] [Green Version]
  31. Jiang, H.; Zhou, Y.; Liao, Q.; Ouyang, H. Helicobacter pylori infection promotes the invasion and metastasis of gastric cancer through increasing the expression of matrix metalloproteinase-1 and matrix metalloproteinase-10. Exp. Ther. Med. 2014, 8, 769–774. [Google Scholar] [CrossRef] [Green Version]
  32. Koyama, S. Significance of cell-surface expression of matrix metalloproteinases and their inhibitors on gastric epithelium and infiltrating mucosal lymphocytes in progression of Helicobacter pylori-associated gastritis. Scand. J. Gastroenterol. 2004, 39, 1046–1053. [Google Scholar] [CrossRef] [PubMed]
  33. Koyama, S. Enhanced cell surface expression of matrix metalloproteinases and their inhibitors, and tumor-induced host response in progression of human gastric carcinoma. Am. J. Dig. Dis. 2004, 49, 1621–1630. [Google Scholar] [CrossRef] [PubMed]
  34. Krueger, S.; Hundertmark, T.; Kalinski, T.; Peitz, U.; Wex, T.; Malfertheiner, P.; Naumann, M.; Roessner, A. Helicobacter pylori Encoding the Pathogenicity Island Activates Matrix Metalloproteinase 1 in Gastric Epithelial Cells via JNK and ERK. J. Biol. Chem. 2006, 281, 2868–2875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Rautelin, H.I.; Oksanen, A.M.; Veijola, L.I.; Sipponen, P.I.; Tervahartiala, T.I.; Sorsa, T.A.; Lauhio, A. Enhanced systemic matrix metalloproteinase response in Helicobacter pylori gastritis. Ann. Med. 2009, 41, 208–215. [Google Scholar] [CrossRef]
  36. Zhao, Z.-S.; Chu, Y.-Q.; Ye, Z.-Y.; Wang, Y.-Y.; Tao, H.-Q. Overexpression of matrix metalloproteinase 11 in human gastric carcinoma and its clinicopathologic significance. Hum. Pathol. 2010, 41, 686–696. [Google Scholar] [CrossRef]
  37. Zheng, J.; Chu, D.; Wang, D.; Zhu, Y.; Zhang, X.; Ji, G.; Zhao, H.; Wu, G.; Du, J.; Zhao, Q. Matrix metalloproteinase-12 is associated with overall survival in Chinese patients with gastric cancer. J. Surg. Oncol. 2012, 107, 746–751. [Google Scholar] [CrossRef]
  38. Costa, A.; Ferreira, R.; Pinto-Ribeiro, I.; Sougleri, I.S.; Oliveira, M.J.; Carreto, L.; Santos, M.; Sgouras, D.N.; Carneiro, F.; Leite, M.; et al. Helicobacter pylori Activates Matrix Metalloproteinase 10 in Gastric Epithelial Cells via EGFR and ERK-mediated Pathways. J. Infect. Dis. 2016, 213, 1767–1776. [Google Scholar] [CrossRef] [Green Version]
  39. Mori, N.; Sato, H.; Hayashibara, T.; Senba, M.; Geleziunas, R.; Wada, A.; Hirayama, T.; Yamamoto, N. Helicobacter pylori induces matrix metalloproteinase-9 through activation of nuclear factor κB. Gastroenterology 2003, 124, 983–992. [Google Scholar] [CrossRef]
  40. Moss, M.L.; Jin, S.-L.C.; Milla, M.E.; Burkhart, W.; Carter, H.L.; Chen, W.-J.; Clay, W.C.; Didsbury, J.R.; Hassler, D.; Hoffman, C.R.; et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 1997, 385, 733–736. [Google Scholar] [CrossRef]
  41. Black, R.A.; Rauch, C.T.; Kozlosky, C.J.; Peschon, J.J.; Slack, J.L.; Wolfson, M.F.; Castner, B.J.; Stocking, K.L.; Reddy, P.; Srinivasan, S.; et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 1997, 385, 729–733. [Google Scholar] [CrossRef]
  42. Clendeninn, N.J.; Appelt, K. Matrix Metalloproteinase Inhibitors in Cancer Therapy; Springer: New York, NY, USA, 2000. [Google Scholar]
  43. Klein, T.; Bischoff, R. Active Metalloproteases of the A Disintegrin And Metalloprotease (ADAM) Family: Biological Function and Structure. J. Proteome Res. 2011, 10, 17–33. [Google Scholar] [CrossRef]
  44. Slomiany, B.L.; Slomiany, A. Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation. Inflammopharmacology 2015, 24, 23–31. [Google Scholar] [CrossRef] [PubMed]
  45. Van den Steen, P.E.; Proost, P.; Wuyts, A.; Van Damme, J.; Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 2000, 96, 2673–2681. [Google Scholar] [CrossRef] [PubMed]
  46. Song, J.; Wu, C.; Zhang, X.; Sorokin, L.M. In Vivo Processing of CXCL5 (LIX) by Matrix Metalloproteinase (MMP)-2 and MMP-9 Promotes Early Neutrophil Recruitment in IL-1β–Induced Peritonitis. J. Immunol. 2012, 190, 401–410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Elkington, P.T.G. Matrix metalloproteinases in destructive pulmonary pathology. Thorax 2006, 61, 259–266. [Google Scholar] [CrossRef] [Green Version]
  48. Xia, X.; Hua, Y.; Hu, P.; Li, J.; Hu, G.; Tang, X. Adhesin HpaA of Helicobacter pylori Promoted Migration of AGS Cells via IL-21 Secretion from HpaA-induced CD4+T Cells. Jundishapur J. Microbiol. 2020, 13, 1–9. [Google Scholar] [CrossRef]
  49. Caruso, R.; Fina, D.; Peluso, I.; Fantini, M.C.; Tosti, C.; Blanco, G.D.V.; Paoluzi, O.A.; Caprioli, F.; Andrei, F.; Stolfi, C.; et al. IL-21 Is Highly Produced in Helicobacter pylori-Infected Gastric Mucosa and Promotes Gelatinases Synthesis. J. Immunol. 2007, 178, 5957–5965. [Google Scholar] [CrossRef] [Green Version]
  50. Gooz, M.; Shaker, M.; Gooz, P.; Smolka, A.J. Interleukin 1beta induces gastric epithelial cell matrix metalloproteinase secretion and activation during Helicobacter pylori infection. Gut 2003, 52, 1250–1256. [Google Scholar] [CrossRef]
  51. Yin, Y.; Grabowska, A.M.; A Clarke, P.; Whelband, E.; Robinson, K.; Argent, R.H.; Tobias, A.; Kumari, R.; Atherton, J.C.; A Watson, S. Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: Links to soluble HB-EGF, gastrin and matrix metalloproteinase-7. Gut 2010, 59, 1037–1045. [Google Scholar] [CrossRef] [Green Version]
  52. Waldum, H.L.; Sagatun, L.; Mjønes, P. Gastrin and Gastric Cancer. Front. Endocrinol. 2017, 8, 1. [Google Scholar] [CrossRef] [Green Version]
  53. McClurg, U.L.; Danjo, K.; King, H.O.; Scott, G.B.; Robinson, P.A.; Crabtree, J.E. Epithelial cell ADAM17 activation by Helicobacter pylori: Role of ADAM17 C-terminus and Threonine-735 phosphorylation. Microbes Infect. 2015, 17, 205–214. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Ii, M.; Yamamoto, H.; Adachi, Y.; Maruyama, Y.; Shinomura, Y. Role of Matrix Metalloproteinase-7 (Matrilysin) in Human Cancer Invasion, Apoptosis, Growth, and Angiogenesis. Exp. Biol. Med. 2006, 231, 20–27. [Google Scholar] [CrossRef] [PubMed]
  55. Yu, W.-H.; Woessner, J.F.; McNeish, J.D.; Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev. 2002, 16, 307–323. [Google Scholar] [CrossRef] [Green Version]
  56. Bergin, P.J.; Raghavan, S.; Svensson, H.; Starckx, S.; Van Aelst, I.; Gjertsson, I.; Opdenakker, G.; Quiding-Järbrink, M. Gastric gelatinase B/matrix metalloproteinase-9 is rapidly increased in Helicobacter felis-induced gastritis. FEMS Immunol. Med Microbiol. 2008, 52, 88–98. [Google Scholar] [CrossRef] [Green Version]
  57. Chakraborty, S.; Stalin, S.; Das, N.; Choudhury, S.T.; Ghosh, S.; Swarnakar, S. The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 2012, 33, 2991–3001. [Google Scholar] [CrossRef] [PubMed]
  58. Kim, S.-J.; Park, Y.S.; Paik, H.-D.; Chang, H.I. Effect of anthocyanins on expression of matrix metalloproteinase-2 in naproxen-induced gastric ulcers. Br. J. Nutr. 2011, 106, 1792–1801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Yeh, Y.-C.; Kuo, H.-Y.; Chang, W.-L.; Yang, H.-B.; Lu, C.-C.; Cheng, H.-C.; Wu, M.-S.; Sheu, B.-S. H. pylori isolates with amino acid sequence polymorphisms as presence of both HtrA-L171 & CagL-Y58/E59 increase the risk of gastric cancer. J. Biomed. Sci. 2019, 26, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Zarzecka, U.; Matkowska, D.; Backert, S.; Skorko-Glonek, J. Importance of two PDZ domains for the proteolytic and chaperone activities of Helicobacter pylori serine protease HtrA. Cell. Microbiol. 2020, 23, e13299. [Google Scholar] [CrossRef]
  61. Zarzecka, U.; Harrer, A.; Zawilak-Pawlik, A.; Skorko-Glonek, J.; Backert, S. Chaperone activity of serine protease HtrA of Helicobacter pylori as a crucial survival factor under stress conditions. Cell Commun. Signal. 2019, 17, 1–18. [Google Scholar] [CrossRef] [Green Version]
  62. Salama, N.R.; Shepherd, B.; Falkow, S. Global Transposon Mutagenesis and Essential Gene Analysis of Helicobacter pylori. J. Bacteriol. 2004, 186, 7926–7935. [Google Scholar] [CrossRef] [Green Version]
  63. Saha, A.; Backert, S.; Hammond, C.E.; Gooz, M.; Smolka, A.J. Helicobacter pylori CagL Activates ADAM17 to Induce Repression of the Gastric H, K-ATPase α Subunit. Gastroenterology 2010, 139, 239–248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Jabłońska-Trypuć, A.; Matejczyk, M.; Rosochacki, S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzym. Inhib. Med. Chem. 2016, 31 (Suppl. S1), 177–183. [Google Scholar] [CrossRef] [Green Version]
  65. Wroblewski, L.E.; Noble, P.-J.M.; Pagliocca, A.; Pritchard, D.M.; Hart, C.A.; Campbell, F.; Dodson, A.R.; Dockray, G.J.; Varro, A. Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: Role in epithelial cell migration. J. Cell Sci. 2003, 116, 3017–3026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Schirrmeister, W.; Gnad, T.; Wex, T.; Higashiyama, S.; Wolke, C.; Naumann, M.; Lendeckel, U. Ectodomain shedding of E-cadherin and c-Met is induced by Helicobacter pylori infection. Exp. Cell Res. 2009, 315, 3500–3508. [Google Scholar] [CrossRef] [PubMed]
  67. Hong, K.-J.; Wu, D.-C.; Cheng, K.-H.; Chen, L.-T.; Hung, W.-C. RECK Inhibits Stemness Gene Expression and Tumorigenicity of Gastric Cancer Cells by Suppressing ADAM-Mediated Notch1 Activation. J. Cell. Physiol. 2013, 229, 191–201. [Google Scholar] [CrossRef] [PubMed]
  68. Najy, A.J.; Day, K.C.; Day, M.L. The Ectodomain Shedding of E-cadherin by ADAM15 Supports ErbB Receptor Activation. J. Biol. Chem. 2008, 283, 18393–18401. [Google Scholar] [CrossRef] [Green Version]
  69. Klessner, J.L.; Desai, B.V.; Amargo, E.V.; Getsios, S.; Green, K.J. EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2. Mol. Biol. Cell 2009, 20, 328–337. [Google Scholar] [CrossRef] [Green Version]
  70. Zeng, R.; Li, X.; Gorodeski, G.I. Estrogen Abrogates Transcervical Tight Junctional Resistance by Acceleration of Occludin Modulation. J. Clin. Endocrinol. Metab. 2004, 89, 5145–5155. [Google Scholar] [CrossRef] [Green Version]
  71. Noe, V.; Fingleton, B.; Jacobs, K.; Crawford, H.; Vermeulen, S.; Steelant, W.; Bruyneel, E.; Matrisian, L.; Mareel, M. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J. Cell Sci. 2001, 114, 111–118. [Google Scholar] [CrossRef]
  72. Przybylo, J.A.; Radisky, D.C. Matrix metalloproteinase-induced epithelial–mesenchymal transition: Tumor progression at Snail’s pace. Int. J. Biochem. Cell Biol. 2007, 39, 1082–1088. [Google Scholar] [CrossRef]
  73. Davies, G.; Jiang, W.; Mason, M.D. Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: A key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion. Clin. Cancer Res. 2001, 7, 3289–3297. [Google Scholar] [PubMed]
  74. Pflugfelder, S.C.; Farley, W.; Luo, L.; Chen, L.Z.; de Paiva, C.S.; Olmos, L.C.; Li, D.-Q.; Fini, M.E. Matrix Metalloproteinase-9 Knockout Confers Resistance to Corneal Epithelial Barrier Disruption in Experimental Dry Eye. Am. J. Pathol. 2005, 166, 61–71. [Google Scholar] [CrossRef] [Green Version]
  75. Symowicz, J.; Adley, B.P.; Gleason, K.J.; Johnson, J.J.; Ghosh, S.; Fishman, D.A.; Hudson, L.G.; Stack, M.S. Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9–Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells. Cancer Res. 2007, 67, 2030–2039. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Lorch, J.H.; Klessner, J.; Park, J.K.; Getsios, S.; Wu, Y.L.; Stack, M.S.; Green, K.J. Epidermal Growth Factor Receptor Inhibition Promotes Desmosome Assembly and Strengthens Intercellular Adhesion in Squamous Cell Carcinoma Cells. J. Biol. Chem. 2004, 279, 37191–37200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Covington, M.D.; Burghardt, R.C.; Parrish, A.R. Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14). Am. J. Physiol. Physiol. 2006, 290, F43–F51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Marques, M.S.; Costa, A.C.; Osório, H.; Pinto, M.L.; Relvas, S.; Dinis-Ribeiro, M.; Carneiro, F.; Leite, M.; Figueiredo, C. Helicobacter pylori PqqE is a new virulence factor that cleaves junctional adhesion molecule A and disrupts gastric epithelial integrity. Gut Microbes 2021, 13, 1–21. [Google Scholar] [CrossRef] [PubMed]
  79. Hoy, B.; Löwer, M.; Weydig, C.; Carra, G.; Tegtmeyer, N.; Geppert, T.; Schröder, P.; Sewald, N.; Backert, S.; Schneider, G.; et al. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 2010, 11, 798–804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Bernegger, S.; Vidmar, R.; Fonovic, M.; Posselt, G.; Turk, B.; Wessler, S. Identification of Desmoglein-2 as a novel target of Helicobacter pylori HtrA in epithelial cells. Cell Commun. Signal. 2021, 19, 1–12. [Google Scholar] [CrossRef]
  81. Tegtmeyer, N.; Wessler, S.; Necchi, V.; Rohde, M.; Harrer, A.; Rau, T.T.; Asche, C.I.; Boehm, M.; Loessner, H.; Figueiredo, C.; et al. Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery. Cell Host Microbe 2017, 22, 552–560.e5. [Google Scholar] [CrossRef] [Green Version]
  82. Steinhusen, U.; Weiske, J.; Badock, V.; Tauber, R.; Bommert, K.; Huber, O. Cleavage and Shedding of E-cadherin after Induction of Apoptosis. J. Biol. Chem. 2001, 276, 4972–4980. [Google Scholar] [CrossRef] [Green Version]
  83. Yang, Y.; Du, J.; Liu, F.; Wang, X.; Li, X.; Li, Y. Role of caspase-3/E-cadherin in Helicobacter pylori-induced apoptosis of gastric epithelial cells. Oncotarget 2017, 8, 59204–59216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Nava, P.; Laukoetter, M.G.; Hopkins, A.; Laur, O.; Gerner-Smidt, K.; Green, K.J.; Parkos, C.A.; Nusrat, A. Desmoglein-2: A Novel Regulator of Apoptosis in the Intestinal Epithelium. Mol. Biol. Cell 2007, 18, 4565–4578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. O’Connor, P.M.; Lapointe, T.K.; Jackson, S.; Beck, P.L.; Jones, N.L.; Buret, A.G. Helicobacter pylori Activates Calpain via Toll-Like Receptor 2 To Disrupt Adherens Junctions in Human Gastric Epithelial Cells. Infect. Immun. 2011, 79, 3887–3894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Yulis, M.; Quirós, M.; Hilgarth, R.; Parkos, C.A.; Nusrat, A. Intracellular Desmoglein-2 cleavage sensitizes epithelial cells to apoptosis in response to pro-inflammatory cytokines. Cell Death Dis. 2018, 9, 389. [Google Scholar] [CrossRef] [Green Version]
  87. Dixon, M.F.; Genta, R.M.; Yardley, J.H.; Correa, P. Classification and Grading of Gastritis. The updated Sydney System. In-ternational Workshop on the Histopathology of Gastritis, Houston 1994. Am. J. Surg. Pathol. 1996, 20, 1161–1181. [Google Scholar] [CrossRef] [PubMed]
  88. Smolka, A.J.; Schubert, M.L. Helicobacter pylori-Induced Changes in Gastric Acid Secretion and Upper Gastrointestinal Disease. Curr. Top. Microbiol. Immunol. 2017, 400, 227–252. [Google Scholar] [CrossRef]
  89. Sáenz, J.B.; Mills, J.C. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 257–273. [Google Scholar] [CrossRef]
  90. Willet, S.; Mills, J.C. Stomach Organ and Cell Lineage Differentiation: From Embryogenesis to Adult Homeostasis. Cell. Mol. Gastroenterol. Hepatol. 2016, 2, 546–559. [Google Scholar] [CrossRef] [Green Version]
  91. Buckley, A.; Turner, J.R. Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease. Cold Spring Harb. Perspect. Biol. 2017, 10, a029314. [Google Scholar] [CrossRef] [PubMed]
  92. Wei, Q.; Huang, H. Insights into the Role of Cell–Cell Junctions in Physiology and Disease. Int. Rev. Cell Mol. Biol. 2013, 306, 187–221. [Google Scholar] [CrossRef] [PubMed]
  93. Zihni, C.; Mills, C.; Matter, K.; Balda, M. Tight junctions: From simple barriers to multifunctional molecular gates. Nat. Rev. Mol. Cell Biol. 2016, 17, 564–580. [Google Scholar] [CrossRef] [PubMed]
  94. Suzuki, T. Regulation of intestinal epithelial permeability by tight junctions. Cell. Mol. Life Sci. 2013, 70, 631–659. [Google Scholar] [CrossRef] [PubMed]
  95. Niessen, C.M.; Leckband, D.; Yap, A.S. Tissue Organization by Cadherin Adhesion Molecules: Dynamic Molecular and Cellular Mechanisms of Morphogenetic Regulation. Physiol. Rev. 2011, 91, 691–731. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Green, K.J.; Jaiganesh, A.; A Broussard, J. Desmosomes: Essential contributors to an integrated intercellular junction network. F1000Research 2019, 8, 2150. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Kowalczyk, A.P.; Green, K.J. Structure, Function, and Regulation of Desmosomes. Prog. Mol. Biol. Transl. Sci. 2013, 116, 95–118. [Google Scholar] [CrossRef] [Green Version]
  98. Kowalczyk, A.P.; Nanes, B.A. Adherens Junction Turnover: Regulating Adhesion Through Cadherin Endocytosis, Degradation, and Recycling. In Adherens Junctions: From Molecular Mechanisms to Tissue Development and Disease; Springer: Berlin/Heidelberg, Germany, 2012; pp. 197–222. [Google Scholar] [CrossRef] [Green Version]
  99. Bhat, A.A.; Uppada, S.; Achkar, I.W.; Hashem, S.; Yadav, S.K.; Shanmugakonar, M.; Al-Naemi, H.A.; Haris, M.; Uddin, S. Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk. Front. Physiol. 2018, 9, 1942. [Google Scholar] [CrossRef] [Green Version]
  100. Wachtel, M.; Frei, K.; Ehler, E.; Fontana, A.; Winterhalter, K.; Gloor, S. Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J. Cell Sci. 1999, 112, 4347–4356. [Google Scholar] [CrossRef]
  101. Gorodeski, G.I. Estrogen Decrease in Tight Junctional Resistance Involves Matrix-Metalloproteinase-7-Mediated Remodeling of Occludin. Endocrinology 2007, 148, 218–231. [Google Scholar] [CrossRef] [Green Version]
  102. Casas, E.; Barron, C.; Francis, S.A.; McCormack, J.M.; McCarthy, K.M.; Schneeberger, E.E.; Lynch, R.D. Cholesterol efflux stimulates metalloproteinase-mediated cleavage of occludin and release of extracellular membrane particles containing its C-terminal fragments. Exp. Cell Res. 2010, 316, 353–365. [Google Scholar] [CrossRef] [Green Version]
  103. Willemsen, L.E.M.; Hoetjes, J.P.; Van Deventer, S.J.H.; Van Tol, E.A.F. Abrogation of IFN-gamma mediated epithelial barrier disruption by serine protease inhibition. Clin. Exp. Immunol. 2005, 142, 275–284. [Google Scholar] [CrossRef]
  104. Lee, L.Y.; Wu, C.M.; Wang, C.C.; Yu, J.S.; Liang, Y.; Huang, K.H.; Lo, C.-H.; Hwang, T.L. Expression of matrix metalloproteinases MMP-2 and MMP-9 in gastric cancer and their relation to claudin-4 expression. Histol. Histopathol. 2008, 515–521. [Google Scholar] [CrossRef]
  105. Honda, M.; Mori, M.; Ueo, H.; Sugimachi, K.; Akiyoshi, T. Matrix metalloproteinase-7 expression in gastric carcinoma. Gut 1996, 39, 444–448. [Google Scholar] [CrossRef] [Green Version]
  106. Kourtidis, A.; Lu, R.; Pence, L.J.; Anastasiadis, P.Z. A central role for cadherin signaling in cancer. Exp. Cell Res. 2017, 358, 78–85. [Google Scholar] [CrossRef] [PubMed]
  107. Bruner, H.C.; Derksen, P.W. Loss of E-Cadherin-Dependent Cell–Cell Adhesion and the Development and Progression of Cancer. Cold Spring Harb. Perspect. Biol. 2017, 10, a029330. [Google Scholar] [CrossRef] [Green Version]
  108. Grabowska, M.M.; Day, M.L. Soluble E-cadherin: More than a symptom of disease. Front. Biosci. 2012, 17, 1948–1964. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Chan, A.O.O.; Lam, S.K.; Chu, K.M.; Lam, C.M.; Kwok, E.; Leung, S.Y.; Yuen, S.T.; Law, S.Y.K.; Hui, W.M.; Lai, K.C.; et al. Soluble E-cadherin is a valid prognostic marker in gastric carcinoma. Gut 2001, 48, 808–811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Maretzky, T.; Reiss, K.; Ludwig, A.; Buchholz, J.; Scholz, F.; Proksch, E.; de Strooper, B.; Hartmann, D.; Saftig, P. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and catenin translocation. Proc. Natl. Acad. Sci. USA 2005, 102, 9182–9187. [Google Scholar] [CrossRef] [Green Version]
  111. Yang, Y.; Li, X.; Du, J.; Yin, Y.; Li, Y. Involvement of microRNAs-MMPs-E-cadherin in the migration and invasion of gastric cancer cells infected with Helicobacter pylori. Exp. Cell Res. 2018, 367, 196–204. [Google Scholar] [CrossRef]
  112. King, I.A.; Angst, B.D.; Hunt, D.M.; Buxton, R.S.; Kruger, M.; Arnemann, J. Hierarchical expression of desmosomal cadherins during stratified epithelial morphogenesis in the mouse. Differentiation 1997, 62, 83–96. [Google Scholar] [CrossRef]
  113. Biedermann, K.; Vogelsang, H.; Becker, I.; Plaschke, S.; Siewert, J.R.; Höfler, H.; Keller, G. Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer. J. Pathol. 2005, 207, 199–206. [Google Scholar] [CrossRef]
  114. Kamekura, R.; Nava, P.; Feng, M.; Quiros, M.; Nishio, H.; Weber, D.A.; Parkos, C.A.; Nusrat, A. Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier. Mol. Biol. Cell 2015, 26, 3165–3177. [Google Scholar] [CrossRef] [PubMed]
  115. Kolegraff, K.; Nava, P.; Laur, O.; Parkos, C.A.; Nusrat, A. Characterization of full-length and proteolytic cleavage fragments of desmoglein-2 in native human colon and colonic epithelial cell lines. Cell Adhes. Migr. 2011, 5, 306–314. [Google Scholar] [CrossRef] [PubMed]
  116. Bergin, P.J.; Anders, E.; Sicheng, W.; Erik, J.; Jennie, A.; Hans, L.; Pierre, M.; Qiang, P.-H.; Marianne, Q.-J. Increased Production of Matrix Metalloproteinases in Helicobacter pylori-Associated Human Gastritis. Helicobacter 2004, 9, 201–210. [Google Scholar] [CrossRef] [PubMed]
  117. Carl-McGrath, S.; Lendeckel, U.; Ebert, M.; Roessner, A.; Röcken, C. The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int. J. Oncol. 2005, 26, 17–24. [Google Scholar] [CrossRef]
  118. Kwok, T.; Zabler, D.; Urman, S.; Rohde, M.; Hartig, R.; Wessler, S.; Misselwitz, R.; Berger, J.; Sewald, N.; König, W.; et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 2007, 449, 862–866. [Google Scholar] [CrossRef]
  119. David, J.; Rajasekaran, A.K. Dishonorable Discharge: The Oncogenic Roles of Cleaved E-Cadherin Fragments. Cancer Res. 2012, 72, 2917–2923. [Google Scholar] [CrossRef] [Green Version]
  120. Martin, T.A. The role of tight junctions in cancer metastasis. Semin. Cell Dev. Biol. 2014, 36, 224–231. [Google Scholar] [CrossRef]
  121. Christiansen, J.J.; Rajasekaran, A.K. Reassessing Epithelial to Mesenchymal Transition as a Prerequisite for Carcinoma Invasion and Metastasis. Cancer Res. 2006, 66, 8319–8326. [Google Scholar] [CrossRef] [Green Version]
  122. Egeblad, M.; Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Cancer 2002, 2, 161–174. [Google Scholar] [CrossRef]
  123. Radisky, D.C.; Levy, D.D.; Littlepage, L.E.; Liu, H.; Nelson, C.M.; Fata, J.E.; Leake, D.; Godden, E.L.; Albertson, D.G.; Nieto, M.A.; et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005, 436, 123–127. [Google Scholar] [CrossRef] [Green Version]
  124. Cai, H.; Jing, C.; Chang, X.; Ding, D.; Han, T.; Yang, J.; Lu, Z.; Hu, X.; Liu, Z.; Wang, J.; et al. Mutational landscape of gastric cancer and clinical application of genomic profiling based on target next-generation sequencing. J. Transl. Med. 2019, 17, 189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Raeeszadeh-Sarmazdeh, M.; Do, L.D.; Hritz, B.G. Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics. Cells 2020, 9, 1313. [Google Scholar] [CrossRef] [PubMed]
  126. Kubben, F.J.G.M.; Sier, C.F.M.; Van Duijn, W.; Griffioen, G.; Hanemaaijer, R.; Van De Velde, C.J.H.; Van Krieken, J.H.J.M.; Lamers, C.B.H.W.; Verspaget, H.W. Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer. Br. J. Cancer 2006, 94, 1035–1040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Shen, W.; Xi, H.; Wei, B.; Chen, L. The prognostic role of matrix metalloproteinase 2 in gastric cancer: A systematic review with meta-analysis. J. Cancer Res. Clin. Oncol. 2014, 140, 1003–1009. [Google Scholar] [CrossRef] [PubMed]
  128. Torii, A.; Kodera, Y.; Uesaka, K.; Hirai, T.; Yasui, K.; Morimoto, T.; Yamamura, Y.; Kato, T.; Hayakawa, T.; Fujimoto, N.; et al. Plasma concentration of matrix metalloproteinase 9 in gastric cancer. Br. J. Surg. 1997, 84, 133–136. [Google Scholar]
  129. Wu, C.-Y.; Wu, M.-S.; Chiang, E.; Chen, Y.-J.; Chen, C.-J.; Chi, N.-H.; Shih, Y.-T.; Chen, G.-H.; Lin, J.-T. Plasma Matrix Metalloproteinase-9 Level Is Better than Serum Matrix Metalloproteinase-9 Level to Predict Gastric Cancer Evolution. Clin. Cancer Res. 2007, 13, 2054–2060. [Google Scholar] [CrossRef] [Green Version]
  130. Liu, H.-Q.; Song, S.; Wang, J.-H.; Zhang, S.-L. Expression of MMP-3 and TIMP-3 in gastric cancer tissue and its clinical significance. Oncol. Lett. 2011, 2, 1319–1322. [Google Scholar] [CrossRef] [Green Version]
  131. Yeh, Y.-C.; Sheu, B.-S.; Cheng, H.-C.; Wang, Y.-L.; Yang, H.-B.; Wu, J.-J. Elevated Serum Matrix Metalloproteinase-3 and -7 in H. pylori-Related Gastric Cancer Can Be Biomarkers Correlating with a Poor Survival. Am. J. Dig. Dis. 2009, 55, 1649–1657. [Google Scholar] [CrossRef]
  132. Lynch, C.C.; Vargo-Gogola, T.; Matrisian, L.M.; Fingleton, B. Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA. J. Oncol. 2010, 2010, 1–11. [Google Scholar] [CrossRef] [Green Version]
  133. Ni, P.; Yu, M.; Zhang, R.; He, M.; Wang, H.; Chen, S.; Duan, G. Prognostic Significance of ADAM17 for Gastric Cancer Survival: A Meta-Analysis. Medicina 2020, 56, 322. [Google Scholar] [CrossRef]
  134. Klein, T.; Bischoff, R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids 2010, 41, 271–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Yan, F.; Cao, H.; Chaturvedi, R.; Krishna, U.; Hobbs, S.S.; Dempsey, P.J.; Peek, R.M.; Cover, T.L.; Washington, M.K.; Wilson, K.T.; et al. Epidermal Growth Factor Receptor Activation Protects Gastric Epithelial Cells From Helicobacter pylori-Induced Apoptosis. Gastroenterology 2009, 136, 1297–1307.e3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Crabtree, J.E.; Jeremy, A.H.; Duval, C.; Dixon, M.F.; Danjo, K.; Carr, I.M.; Pritchard, D.M.; Robinson, P.A. Effects of EGFR Inhibitor on Helicobacter pylori Induced Gastric Epithelial Pathology in Vivo. Pathogens 2013, 2, 571–590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Webster, J.D.; Vucic, D. The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues. Front. Cell Dev. Biol. 2020, 8, 365. [Google Scholar] [CrossRef]
  138. Mannello, F.; Luchetti, F.; Falcieri, E.; Papa, S. Multiple roles of matrix metalloproteinases during apoptosis. Apoptosis 2005, 10, 19–24. [Google Scholar] [CrossRef]
  139. Maubach, G.; Vieth, M.; Boccellato, F.; Naumann, M. Helicobacter pylori-induced NF-κB: Trailblazer for gastric pathophysiology. Trends Mol. Med. 2022. [Google Scholar] [CrossRef] [PubMed]
  140. Gonciarz, W.; Krupa, A.; Hinc, K.; Obuchowski, M.; Moran, A.P.; Gajewski, A.; Chmiela, M. The effect of Helicobacter pylori infection and different H. pylori components on the proliferation and apoptosis of gastric epithelial cells and fibroblasts. PLoS ONE 2019, 14, e0220636. [Google Scholar] [CrossRef] [Green Version]
  141. Hartung, M.L.; Gruber, D.C.; Koch, K.N.; Grüter, L.; Rehrauer, H.; Tegtmeyer, N.; Backert, S.; Müller, A.H. pylori -Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression. Cell Rep. 2015, 13, 70–79. [Google Scholar] [CrossRef] [Green Version]
  142. Maeda, S.; Yoshida, H.; Mitsuno, Y.; Hirata, Y.; Ogura, K.; Shiratori, Y.; Omata, M. Analysis of apoptotic and antiapoptotic signalling pathways induced by Helicobacter pylori. Gut 2002, 50, 771–778. [Google Scholar] [CrossRef]
  143. Devi, S.; A Ansari, S.; Tenguria, S.; Kumar, N.; Ahmed, N. Multipronged regulatory functions of a novel endonuclease (TieA) from Helicobacter pylori. Nucleic Acids Res. 2016, 44, 9393–9412. [Google Scholar] [CrossRef] [Green Version]
  144. Sengupta, N.; Macdonald, T.T. The Role of Matrix Metalloproteinases in Stromal/Epithelial Interactions in the Gut. Physiology 2007, 22, 401–409. [Google Scholar] [CrossRef] [PubMed]
  145. McCracken, K.W.; Catá, E.M.; Crawford, C.M.; Sinagoga, K.L.; Schumacher, M.; Rockich, B.E.; Tsai, Y.-H.; Mayhew, C.; Spence, J.R.; Zavros, Y.; et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 2014, 516, 400–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Bertaux-Skeirik, N.; Feng, R.; Schumacher, M.A.; Li, J.; Mahe, M.M.; Engevik, A.C.; Javier, J.E.; Peek, R.M., Jr.; Ottemann, K.; Orian-Rousseau, V.; et al. CD44 Plays a Functional Role in Helicobacter pylori-induced Epithelial Cell Proliferation. PLoS Pathog. 2015, 11, e1004663. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Xu, M.; Zhou, H.; Zhang, C.; He, J.; Wei, H.; Zhou, M.; Lu, Y.; Sun, Y.; Ding, J.W.; Zeng, J.; et al. ADAM17 promotes epithelial-mesenchymal transition via TGF-β/Smad pathway in gastric carcinoma cells. Int. J. Oncol. 2016, 49, 2520–2528. [Google Scholar] [CrossRef] [PubMed]
  148. Deryugina, E.I.; Quigley, J.P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006, 25, 9–34. [Google Scholar] [CrossRef]
  149. Bergers, G.; Brekken, R.; McMahon, G.; Vu, T.H.; Itoh, T.; Tamaki, K.; Tanzawa, K.; Thorpe, P.; Itohara, S.; Werb, Z.; et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2000, 2, 737–744. [Google Scholar] [CrossRef]
  150. Partyka, R.; Gonciarz, M.; Jałowiecki, P.; Kokocińska, D.; Byrczek, T. VEGF and metalloproteinase 2 (MMP 2) expression in gastric cancer tissue. Med. Sci. Monit. 2012, 18, BR130–BR134. [Google Scholar] [CrossRef] [Green Version]
  151. Webb, A.H.; Gao, B.T.; Goldsmith, Z.K.; Irvine, A.S.; Saleh, N.; Lee, R.P.; Lendermon, J.B.; Bheemreddy, R.; Zhang, Q.; Brennan, R.C.; et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer 2017, 17, 1–11. [Google Scholar] [CrossRef]
  152. Holmberg, C.; Ghesquière, B.; Impens, F.; Gevaert, K.; Kumar, J.D.; Cash, N.; Kandola, S.; Hegyi, P.; Wang, T.C.; Dockray, G.J.; et al. Mapping Proteolytic Processing in the Secretome of Gastric Cancer-Associated Myofibroblasts Reveals Activation of MMP-1, MMP-2, and MMP-3. J. Proteome Res. 2013, 12, 3413–3422. [Google Scholar] [CrossRef]
  153. Blavier, L.; Lazaryev, A.; Shi, X.-H.; Dorey, F.J.; Shackleford, G.M.; DeClerck, Y.A. Stromelysin-1 (MMP-3) is a target and a regulator of Wnt1-induced epithelial-mesenchymal transition (EMT). Cancer Biol. Ther. 2010, 10, 198–208. [Google Scholar] [CrossRef] [Green Version]
  154. Gencer, S.; Cebeci, A.; Irmak-Yazicioglu, M.B. Silencing of the MMP-3 gene by siRNA transfection in gastric cancer AGS cells. J. Gastrointest. Liver Dis. 2011, 20. Available online: https://www.researchgate.net/profile/Salih-Gencer-2/publication/50937198_Silencing_of_the_MMP-3_gene_by_siRNA_transfection_in_gastric_cancer_AGS_cells/links/0912f5146f702501d2000000/Silencing-of-the-MMP-3-gene-by-siRNA-transfection-in-gastric-cancer-AGS-cells.pdf (accessed on 4 January 2022).
  155. Yoo, Y.A.; Kang, M.H.; Lee, H.J.; Kim, B.-H.; Park, J.K.; Kim, H.K.; Kim, J.S.; Oh, S.C. Sonic Hedgehog Pathway Promotes Metastasis and Lymphangiogenesis via Activation of Akt, EMT, and MMP-9 Pathway in Gastric Cancer. Cancer Res. 2011, 71, 7061–7070. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Liu, L.; Ye, Y.; Zhu, X. MMP-9 secreted by tumor associated macrophages promoted gastric cancer metastasis through a PI3K/AKT/Snail pathway. Biomed. Pharmacother. 2019, 117, 109096. [Google Scholar] [CrossRef] [PubMed]
  157. Zheng, H.; Takahashi, H.; Murai, Y.; Cui, Z.; Nomoto, K.; Niwa, H.; Tsuneyama, K.; Takano, Y. Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 2006, 26, 3579–3583. [Google Scholar] [PubMed]
  158. Fu, C.-K.; Chang, W.-S.; Tsai, C.-W.; Wang, Y.-C.; Yang, M.-D.; Hsu, H.-S.; Chao, C.-Y.; Yu, C.-C.; Chen, J.-C.; Pei, J.-S.; et al. The Association of MMP9 Promoter Rs3918242 Genotype With Gastric Cancer. Anticancer Res. 2021, 41, 3309–3315. [Google Scholar] [CrossRef] [PubMed]
  159. Wu, M.-H.; Tsai, Y.-T.; Hua, K.-T.; Chang, K.-C.; Kuo, M.-L.; Lin, M.-T. Eicosapentaenoic acid and docosahexaenoic acid inhibit macrophage-induced gastric cancer cell migration by attenuating the expression of matrix metalloproteinase 10. J. Nutr. Biochem. 2012, 23, 1434–1439. [Google Scholar] [CrossRef]
  160. Kou, Y.-B.; Zhang, S.-Y.; Zhao, B.-L.; Ding, R.; Liu, H.; Li, S. Knockdown of MMP11 Inhibits Proliferation and Invasion of Gastric Cancer Cells. Int. J. Immunopathol. Pharmacol. 2013, 26, 361–370. [Google Scholar] [CrossRef]
  161. Su, C.; Wang, W.; Wang, C. IGF-1-induced MMP-11 expression promotes the proliferation and invasion of gastric cancer cells through the JAK1/STAT3 signaling pathway. Oncol. Lett. 2018, 15, 7000–7006. [Google Scholar] [CrossRef]
  162. Decock, J.; Thirkettle, S.; Wagstaff, L.; Edwards, D.R. Matrix metalloproteinases: Protective roles in cancer. J. Cell. Mol. Med. 2011, 15, 1254–1265. [Google Scholar] [CrossRef] [Green Version]
  163. Li, B.; Lou, G.; Zhou, J. MT1-MMP promotes the proliferation and invasion of gastric carcinoma cells via regulating vimentin and E-cadherin. Mol. Med. Rep. 2019, 19, 2519–2526. [Google Scholar] [CrossRef]
  164. Wang, X.; Meng, Q.; Wang, Y.; Gao, Y. Overexpression of MMP14 predicts the poor prognosis in gastric cancer. Medicine 2021, 100, e26545. [Google Scholar] [CrossRef] [PubMed]
  165. Cevenini, A.; Orrù, S.; Mancini, A.; Alfieri, A.; Buono, P.; Imperlini, E. Molecular Signatures of the Insulin-like Growth Factor 1-mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers. Int. J. Mol. Sci. 2018, 19, 2411. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Baj, J.; Korona-Głowniak, I.; Forma, A.; Maani, A.; Sitarz, E.; Rahnama-Hezavah, M.; Radzikowska, E.; Portincasa, P. Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020, 9, 1055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Blok, P.; E Craanen, M.; Dekker, W.; Tytgat, G.N. Loss of E-cadherin expression in early gastric cancer. Histopathology 1999, 34, 410–415. [Google Scholar] [CrossRef]
  168. Kamikihara, T.; Ishigami, S.; Arigami, T.; Matsumoto, M.; Okumura, H.; Uchikado, Y.; Kita, Y.; Kurahara, H.; Kijima, Y.; Ueno, S.; et al. Clinical implications of N-cadherin expression in gastric cancer. Pathol. Int. 2012, 62, 161–166. [Google Scholar] [CrossRef]
  169. Backert, S.; Schmidt, T.P.; Harrer, A.; Wessler, S. Exploiting the Gastric Epithelial Barrier: Helicobacter pylori’s Attack on Tight and Adherens Junctions. Curr. Top. Microbiol. Immunol. 2017, 400, 195–226. [Google Scholar] [CrossRef]
  170. Brouxhon, S.M.; Kyrkanides, S.; Teng, X.; Athar, M.; Ghazizadeh, S.; Simon, M.; O’Banion, M.K.; Ma, L. Soluble E-cadherin: A critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling. Oncogene 2013, 33, 225–235. [Google Scholar] [CrossRef] [Green Version]
  171. Grabowska, M.M.; Sandhu, B.; Day, M.L. EGF promotes the shedding of soluble E-cadherin in an ADAM10-dependent manner in prostate epithelial cells. Cell. Signal. 2012, 24, 532–538. [Google Scholar] [CrossRef] [Green Version]
  172. Qian, Y.; Wu, X.; Yokoyama, Y.; Okuzaki, D.; Taguchi, M.; Hirose, H.; Wang, J.; Hata, T.; Inoue, A.; Hiraki, M.; et al. E-cadherin-Fc chimera protein matrix enhances cancer stem-like properties and induces mesenchymal features in colon cancer cells. Cancer Sci. 2019, 110, 3520–3532. [Google Scholar] [CrossRef]
  173. Inge, L.J.; Barwe, S.P.; D’Ambrosio, J.; Gopal, J.; Lu, K.; Ryazantsev, S.; Rajasekaran, S.A.; Rajasekaran, A.K. Soluble E-cadherin promotes cell survival by activating epidermal growth factor receptor. Exp. Cell Res. 2011, 317, 838–848. [Google Scholar] [CrossRef]
  174. Weydig, C.; Starzinski-Powitz, A.; Carra, G.; Löwer, J.; Wessler, S. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp. Cell Res. 2007, 313, 3459–3471. [Google Scholar] [CrossRef]
  175. Song, X.; Xin, N.; Wang, W.; Zhao, C. Wnt/β-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis. Oncotarget 2015, 6, 35579–35588. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Ogden, S.R.; Wroblewski, L.E.; Weydig, C.; Romero-Gallo, J.; O’Brien, D.P.; Israel, D.A.; Krishna, U.S.; Fingleton, B.; Reynolds, A.B.; Wessler, S.; et al. p120 and Kaiso Regulate Helicobacter pylori-induced Expression of Matrix Metalloproteinase-7. Mol. Biol. Cell 2008, 19, 4110–4121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Suarez-Carmona, M.; Lesage, J.; Cataldo, D.; Gilles, C. EMT and inflammation: Inseparable actors of cancer progression. Mol. Oncol. 2017, 11, 805–823. [Google Scholar] [CrossRef] [PubMed]
  178. Athauda, G.; Giubellino, A.; Coleman, J.; Horak, C.; Steeg, P.S.; Lee, M.-J.; Trepel, J.; Wimberly, J.; Sun, J.; Coxon, A.; et al. c-Met Ectodomain Shedding Rate Correlates with Malignant Potential. Clin. Cancer Res. 2006, 12, 4154–4162. [Google Scholar] [CrossRef] [Green Version]
  179. Peng, Z. Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J. Gastroenterol. 2014, 20, 5403–5410. [Google Scholar] [CrossRef]
  180. Sternlicht, M.D.; Bissell, M.J.; Werb, Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 2000, 19, 1102–1113. [Google Scholar] [CrossRef] [Green Version]
  181. Foda, H.D.; Zucker, S. Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis. Drug Discov. Today 2001, 6, 478–482. [Google Scholar] [CrossRef]
  182. Zhang, H.; Li, Y.; Xu, G. Human macrophage metalloelastase expression in gastric cancer and its relationship with gastric cancer prognosis. J. Exp. Clin. Cancer Res. 2007, 26, 361–366. [Google Scholar]
  183. Chang, W.-J. Inflammation-related factors predicting prognosis of gastric cancer. World J. Gastroenterol. 2014, 20, 4586–4596. [Google Scholar] [CrossRef]
Ijms 23 02419 g001 550
Figure 1. Proteases in colonization, epithelial inflammation, and epithelial barrier disruption. Colonization of the gastric tissue by H. pylori is positively (green) or negatively (red) affected by the activity of several proteases of human or bacterial origin. Additionally, infection with H. pylori leads to upregulation of proteolytic activities through elevated transcription levels of proteases in epithelial cells, or through the enhanced immune cell infiltrate. These proteases from epithelial, immune cell, or bacterial origin are directly involved in promoting mucosal inflammation and disruption of the gastric epithelial barrier through their involvement in cytokine shedding, degradation of ECM proteins, and opening of lateral cell–cell junctions.TJ, tight junctions; AJ, adherens junctions. Created with BioRender.com.
Figure 1. Proteases in colonization, epithelial inflammation, and epithelial barrier disruption. Colonization of the gastric tissue by H. pylori is positively (green) or negatively (red) affected by the activity of several proteases of human or bacterial origin. Additionally, infection with H. pylori leads to upregulation of proteolytic activities through elevated transcription levels of proteases in epithelial cells, or through the enhanced immune cell infiltrate. These proteases from epithelial, immune cell, or bacterial origin are directly involved in promoting mucosal inflammation and disruption of the gastric epithelial barrier through their involvement in cytokine shedding, degradation of ECM proteins, and opening of lateral cell–cell junctions.TJ, tight junctions; AJ, adherens junctions. Created with BioRender.com.
Ijms 23 02419 g001
Ijms 23 02419 g002 550
Figure 2. Proteases in EMT, tissue transformation, metastasis, and neoangiogenesis. EMT processes and the balance between cell survival and proliferation is influenced by a number of host and H. pylori proteases. At later stages of gastric cancer progression, proteases originating from H. pylori and epithelial cells in concert with proteases derived from tumor-associated immune cells or fibroblasts are directly involved in neoplastic transformation, as well as metastasis and neoangiogenesis. Created with BioRender.com.
Figure 2. Proteases in EMT, tissue transformation, metastasis, and neoangiogenesis. EMT processes and the balance between cell survival and proliferation is influenced by a number of host and H. pylori proteases. At later stages of gastric cancer progression, proteases originating from H. pylori and epithelial cells in concert with proteases derived from tumor-associated immune cells or fibroblasts are directly involved in neoplastic transformation, as well as metastasis and neoangiogenesis. Created with BioRender.com.
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Table
Table 1. Proteases in colonization, epithelial inflammation, and epithelial barrier disruption.
Table 1. Proteases in colonization, epithelial inflammation, and epithelial barrier disruption.
Group/ProteasePutative TargetImportance
Colonization and Mucosal Inflammation
ADAM17proTNF-α [53], TGF-α [44]pro-inflammatory [44,53] response transcriptional repression of the gastric H, K–adenosine triphosphatase α-subunit, reduced acid production [63]
MMP1 (collagenase-1)proTNF-α, proIL-1β [42]pro-inflammatory effect [64]
MMP2 (gelatinase A)CXCL5 [46]neutrophil recruitment [46], upregulated via IL-21 [48,49]
MMP7 (matrilysin-1)proTNF-α [65]
HB-EGF [51,54]		reduced inflammation, dampens the production of the cytokines [22], immune cells infiltration [24]
MMP9 (gelatinase B)CXCL5 [46]neutrophil recruitment [45,46], upregulated via IL-21 [48,49], macrophages infiltration [56], pro-inflammatory and anti-inflammatory activity [64]
MMP10 (stromelysin-2) supports bacterial colonization, fosters tissue inflammation, recruitment of T cells [23]
Hp0169Type I collagencolonization of Mongolian gerbils [21]
HtrA chronic inflammation [59]
Impairment of Junctional Integrity and Epithelial Barrier Function
ADAM10E-cadherin [66]loss of AJ [66], stem-like phenotype in cancer stem cells and supports anchorage independent growth [67]
ADAM15E-cadherin [68]
desmoglein-2 [69]		impaired cell adhesiveness [69]
ADAM17desmoglein-2 [69]impaired cell adhesiveness [69], stem-like phenotype in cancer stem cells and supports anchorage independent growth [67]
MMP2 (gelatinase A)Occludin [70]increase in epithelial or endothelial permeability [70]
MMP3 (stromelysin-1)E-cadherin [71]disintegration of cell-cell junctions, destabilization of cell-ECM interactions [72]
MMP7 (matrilysin-1)E-cadherin [51,71,73]abnormal cell aggregation and increase in cells invasiveness [64]
MMP9 (gelatinase B)Occluding [74]
E-cadherin [75]
desmoglein-2 [76]		impaired cell adhesiveness [76]
MMP14 (MT1-MMP)E-cadherin [77]adhesion reduction [64]
Hp1012JAM-A [78]impaired barrier function, reduced intercellular adhesion and increased invasive potential of epithelial cells [78]
HtrAE-cadherin [79,80]
desmoglein-2 [80]
occludin, claudin [81]		disruption of intercellular junction access to basolateral space [79,80,81]
caspase-3E-cadherin [82,83]
desmoglein-2 [84]
calpainE-cadherin [85]
desmoglein-2 [86]
Table
Table 2. Proteases in EMT, tissue transformation, metastasis, and neoangiogenesis.
Table 2. Proteases in EMT, tissue transformation, metastasis, and neoangiogenesis.
Group/ProteasePutative TargetImportance
Neoplastic Transformation, Proliferation, and Cell Survival
ADAM9 and -15 gastric cancer cell lines proliferation [117]
ADAM10Notch1 [67]stem-like phenotype in cancer stem cells and supports anchorage independent growth [67]
ADAM12 decreases gastric cancer cell lines proliferation [117]
ADAM17HB-EGF [53]
Notch1 [67]		reduces apoptosis [135], poor prognosis in gastric cancer [133], induces pro-survival signaling via the EGFR [44,135,136], cancer stem like phenotype, anchorage-independent growth [67]
MMP7 (matrilysin-1) promotes proliferation in non-transformed epithelial cells [132]
MMP12
(macrophage metalloelastase)		 inversely correlates with disease outcome [37,134]
caspase-3 executioner caspase, activation by caspase-8, -9, or -10 [139], activation induced by H. pylori LPS and induced MMP9 [140], H. pylori induction of anti-apoptotic proteins of the cIAP family to reduce caspase-3-dependent apoptosis [141,142]
caspase-8 initiator caspase, limited proteolytic (including autocatalytic) activity, engaged by death receptors, including tumor necrosis factor receptor 1 (TNFR1) and Fas/CD95 [139], TieA-protein-induced apoptosis [143]
HtrA HtrA L171 variant was enriched in gastric cancer patients and may increase efficiency in basolateral CagA delivery by H pylori and risk for developing gastric cancer [59]
Epithelial-Mesenchymal Transition (EMT), Metastasis and Neo-Angiogenesis
ADAM10E-cadherin [66,110]
c-Met [66]		E-cadherin cleavage induced EMT [144], c-Met-associated pro-oncogenic signaling cascades [145,146]
ADAM17 EMT [147]
MMP2 (gelatinase A) invasive growth, angiogenesis [134,148,149,150,151], cell migration [152], cell proliferation, migration of epithelial cells [64]
MMP3 (stromelysin-1) SNAIL-dependent EMT [72], WNT-induced β-catenin signaling [153], migration [152,154], invasion [154], angiostatin-like fragments, cell proliferation, release of VEGF, upregulation of angiogenesis [64]
MMP7 (matrilysin-1) EMT marker expression [51], migration and invasion capacity [65], proliferation [132], cell differentiation, vasoconstriction and cell growth [64]
MMP9 (gelatinase B) invasive growth [134,148,155,156], angiogenesis [134,148,149,151,157], tumor cell resistance [64], promoter allele Rs3918242 is associated with metastasis [158], tumor-associated macrophages-derived MMP9 supports metastasis in gastric cancer [156]
MMP10 (stromelysin-2) invasion [38], migration [159], tumor-associated macrophages-derived MMP10 promotes cell migration [159]
MMP11 (stromelysin-3) IGF1-dependent invasive potential of gastric cancer cells [160,161], decreases cancer cell sensitivity to NK cells [64]
MMP12
(macrophage metalloelastase)		 angiogenesis [134,162]
MMP14 (MT1-MMP) cell migration, epithelial cell migration, adhesion reduction [64], migration and invasion [163,164]
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Bernegger, S.; Jarzab, M.; Wessler, S.; Posselt, G. Proteolytic Landscapes in Gastric Pathology and Cancerogenesis. Int. J. Mol. Sci. 2022, 23, 2419. https://doi.org/10.3390/ijms23052419

AMA Style

Bernegger S, Jarzab M, Wessler S, Posselt G. Proteolytic Landscapes in Gastric Pathology and Cancerogenesis. International Journal of Molecular Sciences. 2022; 23(5):2419. https://doi.org/10.3390/ijms23052419

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Bernegger, Sabine, Miroslaw Jarzab, Silja Wessler, and Gernot Posselt. 2022. "Proteolytic Landscapes in Gastric Pathology and Cancerogenesis" International Journal of Molecular Sciences 23, no. 5: 2419. https://doi.org/10.3390/ijms23052419

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