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Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 35329

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Special Issue Editor

Dr. Andrea Disanza

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Guest Editor

IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Interests: actin and membrane dynamics; tumor cell migration and invasion
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer metastasis represents an advanced stage of malignancy and is the leading cause of cancer- therapeutic failure and related deaths. Metastasis is a multistep process that includes loss of cell polarity, tissue disorganization, and cancer cell migration and invasion, which are all hallmarks of cancer. To spread through the tissues and disseminate faraway, tumor cells use mechanisms involving several molecular actors: adhesion receptors, receptor tyrosine kinases, cytoskeleton proteins, and adapter and signaling proteins. An overarching feature of malignant progression, particularly in the case of carcinoma (i.e., epithelia-derived solid cancer), is the acquisition of cell migration. Carcinoma can take a variety of different, frequently interchangeable modes of migration that drive the dissemination of individual or collective entities. The concept of migratory plasticity has emerged as dominant in oncology. The intent of this Special Issue on “Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis” is to dissect the molecular mechanisms at the base of cancer cell migration and invasion strategies. Therefore, we warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Dr. Andrea Disanza
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Signaling
Cell polarity
Migration
Invasion
Adhesions
Cell protrusions
Membrane and actin dynamics

Published Papers (12 papers)

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Research

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14 pages, 8479 KiB

Open AccessArticle

Machilin D Promotes Apoptosis and Autophagy, and Inhibits Necroptosis in Human Oral Squamous Cell Carcinoma Cells

by Hyung-Mun Yun, Yoon-Ju Kwon, Eonmi Kim, Hea-Jong Chung and Kyung-Ran Park

Int. J. Mol. Sci. 2023, 24(5), 4576; https://doi.org/10.3390/ijms24054576 - 26 Feb 2023

Cited by 4 | Viewed by 1620

Abstract

Oral squamous cell carcinoma (OSCC) accounts for about 90% of all head and neck cancers, the prognosis is very poor, and there are no effective targeted therapies. Herein, we isolated Machilin D (Mach), a lignin, from the roots of Saururus chinensis (S. chinensis) and assessed its inhibitory effects on OSCC. Herein, Mach had significant cytotoxicity against human OSCC cells and showed inhibitory effects against cell adhesion, migration, and invasion by inhibiting adhesion molecules, including the FAK/Src pathway. Mach suppressed the PI3K/AKT/mTOR/p70S6K pathway and MAPKs, leading to apoptotic cell death. We investigated other modes of programmed cell death in these cells and found that Mach increased LC3I/II and Beclin1 and decreased p62, leading to autophagosomes, and suppressed the necroptosis-regulatory proteins RIP1 and MLKL. Our findings provide evidence that the inhibitory effects of Mach against human YD-10B OSCC cells are related to the promotion of apoptosis and autophagy and inhibition of necroptosis and are mediated via focal adhesion molecules. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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20 pages, 3001 KiB

Open AccessArticle

MiR-199a-3p Induces Mesenchymal to Epithelial Transition of Keratinocytes by Targeting RAP2B

by Moamen Masalha, Tal Meningher, Adi Mizrahi, Aviv Barzilai, Hilla Tabibian-Keissar, Devorah Gur-Wahnon, Iddo Z. Ben-Dov, Joshua Kapenhas, Jasmine Jacob-Hirsch, Raya Leibowitz, Yechezkel Sidi and Dror Avni

Int. J. Mol. Sci. 2022, 23(23), 15401; https://doi.org/10.3390/ijms232315401 - 6 Dec 2022

Cited by 1 | Viewed by 1543

Abstract

Cutaneous squamous cell carcinoma (CSCC) is an epidermal skin cancer that evolves from normal epidermis along several pre-malignant stages. Previously we found specific miRNAs alterations in each step along these stages. miR-199a-3p expression decreases at the transition to later stages. A crucial step for epithelial carcinoma cells to acquire invasive capacity is the disruption of cell–cell contacts and the gain of mesenchymal motile phenotype, a process known as epithelial-to-mesenchymal transition (EMT). This study aims to study the role of decreased expression of miR-199a-3p in keratinocytes’ EMT towards carcinogenesis. First, we measured miR-199a-3p in different stages of epidermal carcinogenesis. Then, we applied Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) assay to search for possible biochemical targets of miR-199a-3p and verified that Ras-associated protein B2 (RAP2B) is a bona-fide target of miR-199a-3p. Next, we analyzed RAP2B expression, in CSCC biopsies. Last, we evaluated possible mechanisms leading to decreased miR-199a-3p expression. miR-199a-3p induces a mesenchymal to epithelial transition (MET) in CSSC cells. Many of the under-expressed genes in CSCC overexpressing miR-199a-3p, are possible targets of miR-199a-3p and play roles in EMT. RAP2B is a biochemical target of miR-199a-3p. Overexpression of miR-199a-3p in CSCC results in decreased phosphorylated focal adhesion kinase (FAK). In addition, inhibiting FAK phosphorylation inhibits EMT marker genes’ expression. In addition, we proved that DNA methylation is part of the mechanism by which miR-199a-3p expression is inhibited. However, it is not by the methylation of miR-199a putative promoter. These findings suggest that miR-199a-3p inhibits the EMT process by targeting RAP2B. Inhibitors of RAP2B or FAK may be effective therapeutic agents for CSCC. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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18 pages, 4003 KiB

Open AccessArticle

Tumor-Intrinsic PD-L1 Exerts an Oncogenic Function through the Activation of the Wnt/β-Catenin Pathway in Human Non-Small Cell Lung Cancer

by Yunxia Ma, Rumyana Marinkova, Miljana Nenkov, Lai Jin, Otmar Huber, Jürgen Sonnemann, Natália Peca, Nikolaus Gaßler and Yuan Chen

Int. J. Mol. Sci. 2022, 23(19), 11031; https://doi.org/10.3390/ijms231911031 - 20 Sep 2022

Cited by 4 | Viewed by 2176

Abstract

Programmed death ligand 1 (PD-L1) strongly inhibits T cell activation, thereby aiding tumors in escaping the immune response. PD-L1 inhibitors have proven to be effective in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). Yet, the knowledge regarding the biological function of tumor-intrinsic PD-L1 in lung cancer remains obscure. In our study, we set the goal of determining the function of PD-L1 using overexpression and knockdown strategies. PD-L1 silencing resulted in decreased migratory and invasive ability of tumor cells, together with attenuated colony-forming capacity. Ectopic expression of PD-L1 showed the opposite effects, along with increased activities of MAPK and Wnt/β-catenin pathways, and the upregulation of Wnt/β-catenin target genes. Additionally, overexpression of PD-L1 was associated with dysregulated cellular and exosomal miRNAs involved in tumor progression and metastasis. In primary lung tumors, immunohistochemistry revealed that both PD1 and PD-L1 were highly expressed in squamous cell carcinoma (SCC) compared to adenocarcinoma (p = 0.045 and p = 0.036, respectively). In SCC, PD1 expression was significantly associated with tumor grading (p = 0.016). Taken together, our data suggest that PD-L1 may exert an oncogenic function in NSCLC through activating Wnt/β-catenin signaling, and may act as a potential diagnostic marker for lung SCC. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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15 pages, 2409 KiB

Open AccessArticle

Infiltration of Apoptotic M2 Macrophage Subpopulation Is Negatively Correlated with the Immunotherapy Response in Colorectal Cancer

by Rui Liu, Chongyin Han, Jiaqi Hu, Baowen Zhang, Wei Luo and Fei Ling

Int. J. Mol. Sci. 2022, 23(19), 11014; https://doi.org/10.3390/ijms231911014 - 20 Sep 2022

Cited by 2 | Viewed by 2274

Abstract

The polarization of tumor-associated macrophages (TAMs) plays a key role in tumor development and immunotherapy in colorectal cancer (CRC) patients. However, the impact of apoptosis on TAM polarization and immunotherapy efficacy in patients with different mismatch repair statuses (MMR) remains unclear. Here, we constructed an atlas of macrophage and found a higher rate of infiltration of M2-like TAM subpopulation in pMMR CRC tumor tissues compared with that in dMMR CRC tumor tissues. Importantly, a lower infiltration rate of M2c-like TAMs was associated with immunotherapy response. The M2 polarization trajectory revealed the apoptosis of M2c-like TAMs in dMMR while the differentiation of M2c-like TAMs in pMMR, implying a higher polarization level of M2 in pMMR. Furthermore, we found that a high expression of S100A6 induces the apoptosis of M2c-like TAMs in dMMR. In conclusion, we identified apoptotic TAM subpopulations in the M2 polarization trajectory and found that apoptosis caused by the high expression of S100A6 reduces their infiltration in tumors as well as the level of M2 polarization and contributes to a favorable immunotherapy response. These findings provide new insights into the potential role of apoptosis in suppressing tumors and enhancing immunotherapeutic efficacy. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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14 pages, 3043 KiB

Open AccessArticle

ARPC1B Is Associated with Lethal Prostate Cancer and Its Inhibition Decreases Cell Invasion and Migration In Vitro

by Yaser Gamallat, Hend Zaaluk, Ealia Khosh Kish, Ramy Abdelsalam, Konstantinos Liosis, Sunita Ghosh and Tarek A. Bismar

Int. J. Mol. Sci. 2022, 23(3), 1476; https://doi.org/10.3390/ijms23031476 - 27 Jan 2022

Cited by 6 | Viewed by 2766

Abstract

ARPC1B (Actin Related Protein 2/3 Complex Subunit 1B) has been found to be involved in platelet abnormalities of immune-mediated inflammatory disease and eosinophilia. However, its role in prostate cancer (PCa) has not been established. We characterized the role of ARPC1B in PCa invasion and metastasis and investigated its prognosis using in vitro cellular models and PCa clinical data. Higher immunohistochemistry (IHC) expressions of ARPC1B were observed in localized and castrate resistant PCa (CRPC) vs. benign prostate tissue (p < 0.01). Additionally, 47% of patients with grade group 5 (GG) showed high ARPC1B expression vs. other GG patients. Assessing ARPC1B expression in association with two of the common genetic aberrations in PCa (ERG and PTEN) showed significant association to overall and cause-specific survival for combined assessment of ARPC1B and PTEN, and ARPC1B and ERG. Knockdown of ARPC1B impaired the migration and invasion of PC3 and DU145 PCa cells via downregulation of Aurora A kinase (AURKA) and resulted in the arrest of the cells in the G2/M checkpoint of the cell cycle. Additionally, higher ARPC1B expression was observed in stable PC3-ERG cells compared to normal PC3, supporting the association between ERG and ARPC1B. Our findings implicate the role of ARPC1B in PCa invasion and metastasis in association with ERG and further support its prognostic value as a biomarker in association with ERG and PTEN in identifying aggressive phenotypes of PCa cancer. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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20 pages, 2319 KiB

Open AccessArticle

Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

by Inés Martínez-Pena, Pablo Hurtado, Nuria Carmona-Ule, Carmen Abuín, Ana Belén Dávila-Ibáñez, Laura Sánchez, Miguel Abal, Anas Chaachou, Javier Hernández-Losa, Santiago Ramón y Cajal, Rafael López-López and Roberto Piñeiro

Int. J. Mol. Sci. 2021, 22(17), 9279; https://doi.org/10.3390/ijms22179279 - 27 Aug 2021

Cited by 10 | Viewed by 4189

Abstract

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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18 pages, 5633 KiB

Open AccessArticle

PML Differentially Regulates Growth and Invasion in Brain Cancer

by Maria Tampakaki, Mariam-Eleni Oraiopoulou, Eleftheria Tzamali, Giorgos Tzedakis, Takis Makatounakis, Giannis Zacharakis, Joseph Papamatheakis and Vangelis Sakkalis

Int. J. Mol. Sci. 2021, 22(12), 6289; https://doi.org/10.3390/ijms22126289 - 11 Jun 2021

Cited by 6 | Viewed by 4123

Abstract

Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro–in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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20 pages, 3523 KiB

Open AccessArticle

The Influence of VE-Cadherin on Adhesion and Incorporation of Breast Cancer Cells into Vascular Endothelium

by Thomas Brock, Elisabeth Boudriot, Anke Klawitter, Marianne Großer, Trang T. P. Nguyen, Sindy Giebe, Erik Klapproth, Achim Temme, Ali El-Armouche and Georg Breier

Int. J. Mol. Sci. 2021, 22(11), 6049; https://doi.org/10.3390/ijms22116049 - 3 Jun 2021

Cited by 7 | Viewed by 2933

Abstract

During metastasis, cancer cells that originate from the primary tumor circulate in the bloodstream, extravasate, and form micrometastases at distant locations. Several lines of evidence suggest that specific interactions between cancer cells and endothelial cells, in particular tumor cell adhesion to the endothelium and transendothelial migration, play a crucial role in extravasation. Here we have studied the role of vascular endothelial (VE)-cadherin which is expressed aberrantly by breast cancer cells and might promote such interactions. By comparing different human breast cancer cell lines, we observed that the number of cancer cells that adhered to endothelium correlated with VE-cadherin expression levels. VE-cadherin silencing experiments confirmed that VE-cadherin enhances cancer cell adhesion to endothelial cells. However, in contrast, the number of cancer cells that incorporated into the endothelium was not dependent on VE-cadherin. Thus, it appears that cancer cell adhesion and incorporation are distinct processes that are governed by different molecular mechanisms. When cancer cells incorporated into the endothelial monolayer, they formed VE-cadherin positive contacts with endothelial cells. On the other hand, we also observed tumor cells that had displaced endothelial cells, reflecting either different modes of incorporation, or a temporal sequence where cancer cells first form contact with endothelial cells and then displace them to facilitate transmigration. Taken together, these results show that VE-cadherin promotes the adhesion of breast cancer cells to the endothelium and is involved in the initial phase of incorporation, but not their transmigration. Thus, VE-cadherin might be of relevance for therapeutic strategies aiming at preventing the metastatic spread of breast cancer cells. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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18 pages, 2473 KiB

Open AccessArticle

KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer

by Luca Jaromi, Veronika Csongei, Monika Vesel, ElHusseiny Mohamed Mahmud Abdelwahab, Amina Soltani, Zsofia Torok, Gabor Smuk, Veronika Sarosi and Judit Erzsebet Pongracz

Int. J. Mol. Sci. 2021, 22(10), 5384; https://doi.org/10.3390/ijms22105384 - 20 May 2021

Cited by 12 | Viewed by 3305

Abstract

Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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19 pages, 2864 KiB

Open AccessArticle

MicroRNA-128 Confers Anti-Endothelial Adhesion and Anti-Migration Properties to Counteract Highly Metastatic Cervical Cancer Cells’ Migration in a Parallel-Plate Flow Chamber

by Pei-Chin Chuang, Chun-Wun Lu, Ching-Chin Tsai, Shun-Hung Tseng and Wen-Hong Su

Int. J. Mol. Sci. 2021, 22(1), 215; https://doi.org/10.3390/ijms22010215 - 28 Dec 2020

Cited by 11 | Viewed by 2231

Abstract

Despite the distant metastasis of cervical cancer cells being a prominent cause of mortality, neither the metastasis capacity nor the in vitro conditions mimicking adhesion of cervical cancer cells to endothelial cells have been fully elucidated. Circulating metastatic cancer cells undergo transendothelial migration and invade normal organs in distant metastasis; however, the putative molecular mechanism remains largely uncertain. In this study, we describe the use of an in vitro parallel-plate flow chamber to simulate the dynamic circulation stress on cervical cancer cells and elucidate their vascular adhesion and metastasis. We isolate the viable and shear stress-resistant (SSR) cervical cancer cells for mechanistic studies. Remarkably, the identified SSR-HeLa and SSR-CaSki exhibited high in vitro adhesive and metastatic activities. Hence, a consistently suppressed miR-128 level was revealed in SSR cell clones compared to those of parental wild-type (WT) cells. Overexpressed miR-128 attenuated SSR-HeLa cells’ adherence to human umbilical cord vein endothelial cells (HUVECs); in contrast, suppressed miR-128 efficiently augmented the static adhesion capacity in WT-HeLa and WT-CaSki cells. Hence, amplified miR-128 modestly abolished in vitro SSR-augmented HeLa and CaSki cell movement, whereas reduced miR-128 aggravated the migration speed in a time-lapse recording assay in WT groups. Consistently, the force expression of miR-128 alleviated the SSR-enhanced HeLa and CaSki cell mobility in a wound healing assay. Notably, miR-128 mediated SSR-enhanced HeLa and CaSki cells’ adhesion and metastasis through suppressed ITGA5, ITGB5, sLex, CEACAM-6, MMP9, and MMP23 transcript levels. Our data provide evidence suggesting that miR-128 is a promising microRNA that prevented endothelial cells’ adhesion and transendothelial migration to contribute to the SSR-enhanced adhesion and metastasis progression under a parallel-plate flow chamber system. This indicates that the nucleoid-based miR-128 strategy may be an attractive therapeutic strategy to eliminate tumor cells resistant to circulation shear flow, prevent vascular adhesion, and preclude subsequent transendothelial metastasis. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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Review

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18 pages, 1808 KiB

Open AccessReview

Multi-Faceted Roles of DNAJB Protein in Cancer Metastasis and Clinical Implications

by Hye-Youn Kim and Suntaek Hong

Int. J. Mol. Sci. 2022, 23(23), 14970; https://doi.org/10.3390/ijms232314970 - 29 Nov 2022

Cited by 7 | Viewed by 2156

Abstract

Heat shock proteins (HSPs) are highly conserved molecular chaperones with diverse cellular activities, including protein folding, assembly or disassembly of protein complexes, and maturation process under diverse stress conditions. HSPs also play essential roles in tumorigenesis, metastasis, and therapeutic resistance across cancers. Among them, HSP40s are widely accepted as regulators of HSP70/HSP90 chaperones and an accumulating number of biological functions as molecular chaperones dependent or independent of either of these chaperones. Despite large numbers of HSP40s, little is known about their physiologic roles, specifically in cancer progression. This article summarizes the multi-faceted role of DNAJB proteins as one subclass of the HSP40 family in cancer development and metastasis. Regulation and deregulation of DNAJB proteins at transcriptional, post-transcriptional, and post-translational levels contribute to tumor progression, particularly cancer metastasis. Furthermore, understanding differences in function and regulating mechanism between DNAJB proteins offers a new perspective on tumorigenesis and metastasis to improve therapeutic opportunities for malignant diseases. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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14 pages, 2141 KiB

Open AccessReview

Targeting WASF3 Signaling in Metastatic Cancer

by Reid Loveless and Yong Teng

Int. J. Mol. Sci. 2021, 22(2), 836; https://doi.org/10.3390/ijms22020836 - 15 Jan 2021

Cited by 13 | Viewed by 4084

Abstract

Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a Wiskott–Aldrich syndrome protein family member, appears to play a major role not only in the regulation of actin cytoskeleton dynamics but also in cancer cell invasion/metastasis. Recent studies have highlighted that WASF3 is a master regulator and acts as a pivotal scaffolding protein, bringing the various components of metastatic signaling complexes together both spatially and temporally. Herein, targeting WASF3 at the levels of transcription, protein stability, and phosphorylation holds great promise for metastasis suppression, regardless of the diverse genetic backgrounds associated with tumor development. This review focuses on the critical and distinct contributions of WASF3 in the regulation of signal pathways promoting cancer cell invasion and metastasis. Full article

(This article belongs to the Special Issue Molecular Regulation of Cancer Cell Migration, Invasion, and Metastasis)

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