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Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 32530

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Dr. Valli De Re

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Immunopathology and Oncological Biomarkers (IBO) Lab, Department of Translational Research and Advanced Diagnostics of Tumors (DRDT), Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy
Interests: biology of cancers of the gastrointestinal tract; Hodgkin's lymphoma, with a focus on infectious and autoimmune related factors
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issues "Molecular Features Distinguishing Gastric Cancer Subtypes" and "Gastric Cancers: Molecular Pathways and Candidate Biomarkers".
Although there has been progress in gastric cancer and a worldwide decline in pathology, gastric cancer remains a disease characterized by an uncontrolled growth and a high mortality mostly due to a delay in diagnosis. The epidemiology of gastric cancer changed in the last 25 years, with a decline of the intestinal type and stomach antral localization but an increase in young people and the diffuse type. The introduction of high-throughput technologies in recent decades that are able to analyse several gastric cancer from small biological samples has caused significant advances in the development of biomarkers in oncology. Molecular pathways and biomarkers molecules are potentially useful for GC diagnosis, because they increase the accuracy of diagnosis (e.g., the nanomolecule used in confocal laser endomicroscopy) and can be used to select patients at risk for GC at an early stage (e.g., ABC pepsinogen test in japan), as well as to propose new GC classification (e.g., TCAG, ACRG). This research has produced important results that enable us to better understand gastric cancer pathogenesis and individualized important targetable molecules to achieve novel drug targets and new treatment strategies in advanced gastric cancer. Target therapies are now ongoing with moderate benefits in some subsets of gastric cancer, but several trials are ongoing to achieve an increase in the survival benefit of patients with gastric cancer. The aim of this Special Issue is to provide new findings regarding molecular pathways and biomarkers that could improve the diagnosis and/or the prognostic classification of gastric cancer, and to resume their potential application in GC detection and classification, or in clinics.

Dr. Valli De Re
Guest Editor

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Keywords

gastric cancer
pathogenesis
immune response
Helicobacter pylori
genomics
proteomics
diagnostic marker
prognostic marker

Related Special Issues

Gastric Cancer: Molecular Pathways and Candidate Biomarkers 4.0 in International Journal of Molecular Sciences (9 articles)
Gastric Cancer: Molecular Pathways and Candidate Biomarkers 5.0 in International Journal of Molecular Sciences (1 article)

Published Papers (10 papers)

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Research

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15 pages, 2762 KiB

Open AccessArticle

Upregulation of LAMB1 via ERK/c-Jun Axis Promotes Gastric Cancer Growth and Motility

by Hana Lee, Won-Jin Kim, Hyeon-Gu Kang, Jun-Ho Jang, Il Ju Choi, Kyung-Hee Chun and Seok-Jun Kim

Int. J. Mol. Sci. 2021, 22(2), 626; https://doi.org/10.3390/ijms22020626 - 10 Jan 2021

Cited by 25 | Viewed by 3873

Abstract

Gastric cancer is the fifth most common cancer worldwide with a poor survival rate. Therefore, it is important to identify predictive and prognostic biomarkers of gastric cancer. Laminin subunit beta 1 (LAMB1) is involved in attachment, migration, and organization during development, and its elevated expression has been associated with several cancers. However, the role and mechanism of LAMB1 in gastric cancer remains unknown. Here, we determined that LAMB1 is upregulated in gastric cancer tissues and contributes to cell growth and motility. Using a public database, we showed that LAMB1 expression was significantly upregulated in gastric cancer compared to normal tissues. LAMB1 was also found to be associated with poor prognosis in patients with gastric cancer. Overexpression of LAMB1 elevated cell proliferation, invasion, and migration; however, knockdown of LAMB1 decreased these effects in gastric cancer cells. U0126, an extracellular signal-regulated kinase (ERK) inhibitor, regulated the expression of LAMB1 in gastric cancer cells. Additionally, we showed that c-Jun directly binds to the LAMB1 promoter as a transcription factor and regulates its gene expression via the ERK pathway in gastric cancer cells. Therefore, our study indicates that LAMB1 promotes cell growth and motility via the ERK/c-Jun axis and is a potential biomarker and therapeutic target of gastric cancer. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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17 pages, 3408 KiB

Open AccessArticle

Gastric Adenocarcinomas and Signet-Ring Cell Carcinoma: Unraveling Gastric Cancer Complexity through Microbiome Analysis—Deepening Heterogeneity for a Personalized Therapy

by Gloria Ravegnini, Bruno Fosso, Viola Di Saverio, Giulia Sammarini, Federica Zanotti, Giulio Rossi, Monica Ricci, Federica D’Amico, Giorgia Valori, Antonella Ioli, Silvia Turroni, Patrizia Brigidi, Patrizia Hrelia and Sabrina Angelini

Int. J. Mol. Sci. 2020, 21(24), 9735; https://doi.org/10.3390/ijms21249735 - 20 Dec 2020

Cited by 22 | Viewed by 3164

Abstract

Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. With the advances of the omic studies, a heterogeneous GC landscape has been revealed, with significant molecular diversity. Given the multifaceted nature of GC, identification of different patient subsets with prognostic and/or predictive outcomes is a key aspect to allow tailoring of specific treatments. Recently, the involvement of the microbiota in gastric carcinogenesis has been described. To deepen this aspect, we compared microbiota composition in signet-ring cell carcinoma (SRCC) and adenocarcinoma (ADC), two distinct GC subtypes. To this purpose, 10 ADC and 10 SRCC and their paired non-tumor (PNT) counterparts were evaluated for microbiota composition through 16S rRNA analysis. Weighted and unweighted UniFrac and Bray–Curtis dissimilarity showed significant community-level separation between ADC and SRCC. Through the LEfSe (linear discriminant analysis coupled with effect size) tool, we identified potential microbial biomarkers associated with GC subtypes. In particular, SRCCs were significantly enriched in the phyla Fusobacteria, Bacteroidetes, Patescibacteria, whereas in the ADC type, Proteobacteria and Acidobacteria phyla were found. Overall, our data add new insights into GC heterogeneity and may contribute to deepening the GC classification. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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15 pages, 2838 KiB

Open AccessArticle

The Reprimo-Like Gene Is an Epigenetic-Mediated Tumor Suppressor and a Candidate Biomarker for the Non-Invasive Detection of Gastric Cancer

by María Alejandra Alarcón, Wilda Olivares, Miguel Córdova-Delgado, Matías Muñoz-Medel, Tomas de Mayo, Gonzalo Carrasco-Aviño, Ignacio Wichmann, Natalia Landeros, Julio Amigo, Enrique Norero, Franz Villarroel-Espíndola, Arnoldo Riquelme, Marcelo Garrido, Gareth I. Owen and Alejandro H. Corvalán

Int. J. Mol. Sci. 2020, 21(24), 9472; https://doi.org/10.3390/ijms21249472 - 12 Dec 2020

Cited by 11 | Viewed by 2812

Abstract

Reprimo-like (RPRML) is an uncharacterized member of the Reprimo gene family. Here, we evaluated the role of RPRML and whether its regulation by DNA methylation is a potential non-invasive biomarker of gastric cancer. RPRML expression was evaluated by immunohistochemistry in 90 patients with gastric cancer and associated with clinicopathologic characteristics and outcomes. The role of RPRML in cancer biology was investigated in vitro, through RPRML ectopic overexpression. Functional experiments included colony formation, soft agar, MTS, and Ki67 immunofluorescence assays. DNA methylation-mediated silencing was evaluated by the 5-azacytidine assay and direct bisulfite sequencing. Non-invasive detection of circulating methylated RPRML DNA was assessed in 25 gastric cancer cases and 25 age- and sex-balanced cancer-free controls by the MethyLight assay. Downregulation of RPRML protein expression was associated with poor overall survival in advanced gastric cancer. RPRML overexpression significantly inhibited clonogenic capacity, anchorage-independent growth, and proliferation in vitro. Circulating methylated RPRML DNA distinguished patients with gastric cancer from controls with an area under the curve of 0.726. The in vitro overexpression results and the poor patient survival associated with lower RPRML levels suggest that RPRML plays a tumor-suppressive role in the stomach. Circulating methylated RPRML DNA may serve as a biomarker for the non-invasive detection of gastric cancer. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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13 pages, 1772 KiB

Open AccessArticle

Prostaglandin E₂ Pathway Is Dysregulated in Gastric Adenocarcinoma in a Caucasian Population

by Catarina Lopes, Carina Pereira, Mónica Farinha, Rui Medeiros and Mário Dinis-Ribeiro

Int. J. Mol. Sci. 2020, 21(20), 7680; https://doi.org/10.3390/ijms21207680 - 16 Oct 2020

Cited by 4 | Viewed by 2536

Abstract

Gastric cancer (GC) represents the third leading cause of cancer-related deaths worldwide. The levels of prostaglandin E₂, a key player in the hallmarks of cancer, are mainly regulated by prostaglandin-endoperoxide synthase 2 (PTGS2) and ATP-binding cassette subfamily C member 4 (ABCC4), involved in its synthesis and exportation, respectively, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and solute carrier organic anion transporter family member 2A1 (SLCO2A1), responsible for its inactivation. Even though there are distinct molecular signatures across ethnic populations, most published studies focus on Asian populations. Our main aim was to explore the genetic expression of the aforementioned molecules in a Caucasian population. 94 “Normal” and 89 tumoral formalin-fixed paraffin-embedded (FFPE) samples from GC patients were used to assess the mRNA expression of PTGS2, ABCC4, hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), SLCO2A1 by Real-Time PCR. We found an upregulation for the PTGS2 gene mean factor of 2.51 and a downregulation for the HPGD and SLCO2A1 genes (mean factor of 0.10 and 0.37, respectively) in tumorous mucosa in a gender-independent manner. In females, we observed an ABCC4 downregulation and a PTGS2 mRNA upregulation compared to males in tumoral mucosa (mean factor of 0.61 and 1.64, respectively). We reported dysregulation of the inflammation triggered PGE₂ pathway in a Caucasian population with an intermediate risk for GC, which might highlight the applicability of aspirin in the treatment of GC patients. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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19 pages, 3915 KiB

Open AccessArticle

The Ubiquitin Gene Expression Pattern and Sensitivity to UBB and UBC Knockdown Differentiate Primary 23132/87 and Metastatic MKN45 Gastric Cancer Cells

by Emanuele Salvatore Scarpa, Filippo Tasini, Rita Crinelli, Chiara Ceccarini, Mauro Magnani and Marzia Bianchi

Int. J. Mol. Sci. 2020, 21(15), 5435; https://doi.org/10.3390/ijms21155435 - 30 Jul 2020

Cited by 17 | Viewed by 3456

Abstract

Gastric cancer (GC) is one of the most common and lethal cancers. Alterations in the ubiquitin (Ub) system play key roles in the carcinogenetic process and in metastasis development. Overexpression of transcription factors YY1, HSF1 and SP1, known to regulate Ub gene expression, is a predictor of poor prognosis and shorter survival in several cancers. In this study, we compared a primary (23132/87) and a metastatic (MKN45) GC cell line. We found a statistically significant higher expression of three out of four Ub coding genes, UBC, UBB and RPS27A, in MKN45 compared to 23132/87. However, while the total Ub protein content and the distribution of Ub between the conjugated and free pools were similar in these two GC cell lines, the proteasome activity was higher in MKN45. Ub gene expression was not affected upon YY1, HSF1 or SP1 small interfering RNA (siRNA) transfection, in both 23132/87 and MKN45 cell lines. Interestingly, the simultaneous knockdown of UBB and UBC mRNAs reduced the Ub content in both cell lines, but was more critical in the primary GC cell line 23132/87, causing a reduction in cell viability due to apoptosis induction and a decrease in the oncoprotein and metastatization marker β-catenin levels. Our results identify UBB and UBC as pro-survival genes in primary gastric adenocarcinoma 23132/87 cells. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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21 pages, 2368 KiB

Open AccessArticle

Distinct Local and Systemic Molecular Signatures in the Esophageal and Gastric Cancers: Possible Therapy Targets and Biomarkers for Gastric Cancer

by Iwona Bednarz-Misa, Paulina Fortuna, Dorota Diakowska, Natalia Jamrozik and Małgorzata Krzystek-Korpacka

Int. J. Mol. Sci. 2020, 21(12), 4509; https://doi.org/10.3390/ijms21124509 - 25 Jun 2020

Cited by 20 | Viewed by 2743

Abstract

Gastric (GC) and esophageal (EC) cancers are highly lethal. Better understanding of molecular abnormalities is needed for new therapeutic targets and biomarkers to be found. Expression of 18 cancer-related genes in 31 paired normal-tumor samples was quantified by reversely-transcribed quantitative polymerase chain reaction (RTqPCR) and systemic concentration of 27 cytokines/chemokines/growth factors in 195 individuals was determined using Luminex xMAP technology. Only Ki67, CLDN2, and BCLxL were altered in GC while Ki67, CDKN1A, ODC1, SLC2A1, HIF1A, VEGFA, NOS2, CCL2, PTGS2, IL10, IL10Ra, and ACTA2 were changed in EC. The relatively unaltered molecular GC landscape resulted from high expression of BCLxL, CDKN1A, BCL2, Ki67, HIF1A, VEGFA, ACTA2, TJP1, CLDN2, IL7Ra, ODC1, PTGS2, and CCL2 in non-cancerous tissue. The NOS2 expression and IL-4, IL-9, FGF2, and RANTES secretion were higher in cardiac than non-cardiac GC. Four-cytokine panels (interleukin (IL)-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13) differentiated GC from benign conditions with 87–89% accuracy. Our results showed increased proliferative, survival, inflammatory and angiogenic capacity in gastric tumor-surrounding tissue, what might contribute to GC aggressiveness and facilitate cancer recurrence. Further studies are needed to determine the CLDN2 and NOS2 suitability as candidate molecular targets in GC and cardiac GC, respectively, and discern the role of CLDN2 or to verify IL-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13 usefulness as differential biomarkers. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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11 pages, 1625 KiB

Open AccessArticle

Role of Metastasis-Related Genes in Cisplatin Chemoresistance in Gastric Cancer

by Yukiko Nishiguchi, Naohide Oue, Rina Fujiwara-Tani, Takamitsu Sasaki, Hitoshi Ohmori, Shingo Kishi, Shiori Mori, Takuya Mori, Naoya Ikeda, Sohei Matsumoto, Kohei Wakatsuki, Yi Luo, Wataru Yasui, Masayuki Sho and Hiroki Kuniyasu

Int. J. Mol. Sci. 2020, 21(1), 254; https://doi.org/10.3390/ijms21010254 - 30 Dec 2019

Cited by 17 | Viewed by 2843

Abstract

The role of metastasis-related genes in cisplatin (CDDP) chemoresistance in gastric cancer is poorly understood. Here, we examined the expression of four metastasis-related genes (namely, c-met, HMGB1, RegIV, PCDHB9) in 39 cases of gastric cancer treated with neoadjuvant therapy with CDDP or CDDP+5-fluorouracil and evaluated its association with CDDP responsiveness. Comparison of CDDP-sensitive cases with CDDP-resistant cases, the expression of c-met, HMGB1, and PCDHB9 was correlated with CDDP resistance. Among them, the expression of HMGB1 showed the most significant correlation with CDDP resistance in multivariate analysis. Treatment of TMK-1 and MKN74 human gastric cancer cell lines with ethyl pyruvate (EP) or tanshinone IIA (TAN), which are reported to inhibit HMGB1 signaling, showed a 4–5-fold increase in inhibition by CDDP. Treatment with EP or TAN also suppressed the expression of TLR4 and MyD88 in the HMGB1 signal transduction pathway and suppressed the activity of NFκB in both cell lines. These results suggest that the expression of these cancer metastasis-related genes is also related to anticancer drug resistance and that suppression of HMGB1 may be particularly useful for CDDP sensitization. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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Review

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12 pages, 3727 KiB

Open AccessReview

Correct Identification of Cell of Origin May Explain Many Aspects of Cancer: The Role of Neuroendocrine Cells as Exemplified from the Stomach

by Helge Waldum and Patricia G. Mjønes

Int. J. Mol. Sci. 2020, 21(16), 5751; https://doi.org/10.3390/ijms21165751 - 11 Aug 2020

Cited by 7 | Viewed by 3631

Abstract

Cancers are believed to originate from stem cells. Previously, the hypothesis was that tumors developed due to dedifferentiation of mature cells. We studied the regulation of gastric acid secretion and showed that gastrin through the gastrin receptor stimulates enterochromaffin-like (ECL) cell histamine release and proliferation. In animal and human studies, we and others showed that long-term hypergastrinemia results in ECL cell-derived tumor through a sequence of hyperplasia, dysplasia, neuroendocrine tumors (NETs), and possibly neuroendocrine carcinomas (NECs) and adenocarcinomas of diffuse type. Perhaps, other cancers may also have their origin in differentiated cells. Knowledge of the growth regulation of the cell of origin is important in cancer prophylaxis and treatment. Physiology plays a central role in carcinogenesis through hormones and other growth factors. Every cell division implies a small risk of mutation; thus mitogens are also mutagens. Moreover, metastasis of slow proliferating cells may also explain so-called tumor dormancy and late recurrence. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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24 pages, 1568 KiB

Open AccessReview

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

by Jacek Baj, Karolina Brzozowska, Alicja Forma, Amr Maani, Elżbieta Sitarz and Piero Portincasa

Int. J. Mol. Sci. 2020, 21(7), 2544; https://doi.org/10.3390/ijms21072544 - 06 Apr 2020

Cited by 32 | Viewed by 4751

Abstract

Infection with Helicobacter pylori, a Gram-negative, microaerophilic pathogen often results in gastric cancer in a subset of affected individuals. This explains why H. pylori is the only bacterium classified as a class I carcinogen by the World Health Organization. Several studies have pinpointed mechanisms by which H. pylori alters signaling pathways in the host cell to cause diseases. In this article, the authors have reviewed 234 studies conducted over a span of 18 years (2002–2020). The studies investigated the various mechanisms associated with gastric cancer induction. For the past 1.5 years, researchers have discovered new mechanisms contributing to gastric cancer linked to H. pylori etiology. Alongside alteration of the host signaling pathways using oncogenic CagA pathways, H. pylori induce DNA damage in the host and alter the methylation of DNA as a means of perturbing downstream signaling. Also, with H. pylori, several pathways in the host cell are activated, resulting in epithelial-to-mesenchymal transition (EMT), together with the induction of cell proliferation and survival. Studies have shown that H. pylori enhances gastric carcinogenesis via a multifactorial approach. What is intriguing is that most of the targeted mechanisms and pathways appear common with various forms of cancer. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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7 pages, 1276 KiB

Open AccessCase Report

Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

by Laura Caggiari, Mara Fornasarig, Mariangela De Zorzi, Renato Cannizzaro, Agostino Steffan and Valli De Re

Int. J. Mol. Sci. 2020, 21(14), 4904; https://doi.org/10.3390/ijms21144904 - 11 Jul 2020

Cited by 1 | Viewed by 1999

Abstract

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families. Full article

(This article belongs to the Special Issue Gastric Cancers: Molecular Pathways and Candidate Biomarkers 3.0)

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