Overexpression of DDR1 Promotes Migration, Invasion, Though EMT-Related Molecule Expression and COL4A1/DDR1/MMP-2 Signaling Axis

Overview

Journal Technol Cancer Res Treat

Specialties Biomedical Engineering
Oncology
Pharmacology

Date 2020 Nov 25

PMID 33234027

Citations 9

Authors

Xin Xie

Hongchao He

Ning Zhang

Xiaojing Wang

Wenbin Rui

Danfeng Xu

Yu Zhu

Affiliations

Soon will be listed here.

Abstract

Purpose: Discoidin domain receptor 1 (DDR1) belongs to a novel class of receptor tyrosine kinases. Previous evidence indicates that DDR1 overexpression promotes the aggressive growth of bladder cancer (BC) cells. This study aimed to investigate the molecular mechanisms by which DDR1 influences BC.

Methods: DDR1 was transfected into human BC RT4 cells. DDR1, COL4A1, and MMP-2 expression in 30 BC tissues and paired adjacent tissues were examined by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Transwell assays were conducted to determine cell migration and invasion. RT-PCR and western blot (WB) were also used to measure the DDR1, COL4A1, MMP-2, and EMT-related gene (ZEB1 and SLUG) expression in RT4 cells after DDR1 overexpression.

Results: COL4A1 and MMP-2 interacted with DDR1 in the PPI network. RT-PCR and immunohistochemistry results showed that both mRNA and protein levels of DDR1 and COL4A1 were significantly increased in BC tissue, while the expression of MMP-2 was increased only at the mRNA level ( < 0.05). Overexpression of DDR1 in RT4 cells significantly promoted their migratory and invasive capabilities ( < 0.05). Moreover, overexpression of DDR1 in RT4 cells increased the mRNA and protein expression of ZEB1, SLUG, COL4A1, and MMP-2 ( < 0.01). DDR1-mediated migration and invasion of RT4 cells were reversed after COL4A1-siRNA treatment.

Conclusion: DDR1 may be a potential therapeutic target in BC patients.

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References

Yeh Y, Lin H, Tang M . Dichotomy of the function of DDR1 in cells and disease progression. Biochim Biophys Acta Mol Cell Res. 2019; 1866(11):118473. DOI: 10.1016/j.bbamcr.2019.04.003. View

Kadler K, Baldock C, Bella J, Boot-Handford R . Collagens at a glance. J Cell Sci. 2007; 120(Pt 12):1955-8. DOI: 10.1242/jcs.03453. View

Krebs A, Mitschke J, Losada M, Schmalhofer O, Boerries M, Busch H . The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017; 19(5):518-529. DOI: 10.1038/ncb3513. View

Veidal S, Karsdal M, Nawrocki A, Larsen M, Dai Y, Zheng Q . Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair. 2011; 4:22. PMC: 3204229. DOI: 10.1186/1755-1536-4-22. View

Parkin J, San Antonio J, Pedchenko V, Hudson B, Jensen S, Savige J . Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes. Hum Mutat. 2011; 32(2):127-43. PMC: 4800984. DOI: 10.1002/humu.21401. View

Manshouri R, Coyaud E, Kundu S, Peng D, Stratton S, Alton K . ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer. Nat Commun. 2019; 10(1):5125. PMC: 6851102. DOI: 10.1038/s41467-019-12832-z. View

Itoh Y . Discoidin domain receptors: Microenvironment sensors that promote cellular migration and invasion. Cell Adh Migr. 2018; 12(4):378-385. PMC: 6363040. DOI: 10.1080/19336918.2018.1460011. View

Wang J, Chen L, Li Y, Guan X . Overexpression of cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. PLoS One. 2011; 6(9):e24967. PMC: 3178578. DOI: 10.1371/journal.pone.0024967. View

Leitinger B . Discoidin domain receptor functions in physiological and pathological conditions. Int Rev Cell Mol Biol. 2014; 310:39-87. PMC: 4021107. DOI: 10.1016/B978-0-12-800180-6.00002-5. View

10.

Xin Y, Bian B, Yang X, Cui W, Cui H, Cui Y . POU5F1 enhances the invasiveness of cancer stem-like cells in lung adenocarcinoma by upregulation of MMP-2 expression. PLoS One. 2014; 8(12):e83373. PMC: 3875455. DOI: 10.1371/journal.pone.0083373. View

11.

Kim S, Lee S, Lee E, Lim H, Shin J, Jung J . Sex-biased differences in the correlation between epithelial-to-mesenchymal transition-associated genes in cancer cell lines. Oncol Lett. 2019; 18(6):6852-6868. PMC: 6876332. DOI: 10.3892/ol.2019.11016. View

12.

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

13.

Sun Y, Song G, Sun N, Chen J, Yang S . Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis. Oncol Lett. 2014; 7(6):1936-1940. PMC: 4049749. DOI: 10.3892/ol.2014.2037. View

14.

Saby C, Collin G, Sinane M, Buache E, Van Gulick L, Saltel F . DDR1 and MT1-MMP Expression Levels Are Determinant for Triggering BIK-Mediated Apoptosis by 3D Type I Collagen Matrix in Invasive Basal-Like Breast Carcinoma Cells. Front Pharmacol. 2019; 10:462. PMC: 6509437. DOI: 10.3389/fphar.2019.00462. View

15.

Zhang Y, Weinberg R . Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018; 12(4):361-373. PMC: 6186394. DOI: 10.1007/s11684-018-0656-6. View

16.

Xie X, Rui W, He W, Shao Y, Sun F, Zhou W . Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer. Am J Transl Res. 2017; 9(5):2500-2507. PMC: 5446532. View

17.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

18.

Turati F, Bosetti C, Polesel J, Serraino D, Montella M, Libra M . Family history of cancer and the risk of bladder cancer: A case-control study from Italy. Cancer Epidemiol. 2017; 48:29-35. DOI: 10.1016/j.canep.2017.03.003. View

19.

Sun J, Zhao L, Yang Y, Ma X, Wang Y, Xiang Y . Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies. PLoS One. 2015; 10(3):e0119313. PMC: 4372289. DOI: 10.1371/journal.pone.0119313. View

20.

Yang Y, Wang F, Huang H, Zhang Y, Xie H, Men T . lncRNA SLCO4A1-AS1 promotes growth and invasion of bladder cancer through sponging miR-335-5p to upregulate OCT4. Onco Targets Ther. 2019; 12:1351-1358. PMC: 6389014. DOI: 10.2147/OTT.S191740. View