Suppression of CD81 Promotes Bladder Cancer Cell Invasion Through Increased Matrix Metalloproteinase Expression Via Extracellular Signal-regulated Kinase Phosphorylation

Overview

Journal Investig Clin Urol

Specialty Urology

Date 2019 Sep 11

PMID 31501803

Citations 6

Authors

Hyun Sik Park

Suhyuk Lee

Jisu Lee

Hyun Bin Shin

Seung-Min Yoo

Myung-Shin Lee

Jinsung Park

Affiliations

Soon will be listed here.

Abstract

Purpose: CD81 is a prognostic biomarker for high-grade bladder cancer (BC). In this study, we aimed to determine the functional mechanisms underlying the role of CD81 in BC progression.

Materials And Methods: In two invasive BC cell lines (T24, J82), CD81 expression was suppressed by the transfection of lentiviral vectors including CD81-specific shRNAs, and then the migration and invasion of BC cells was analyzed. Enzymatic activity of matrix metalloproteinases (MMPs) was also analyzed by collagen-zymography. The expression of MMPs was confirmed by western blotting using culture supernatants from each cell line. Signaling pathways related to MMPs were investigated using various antibodies.

Results: CD81 was successfully knocked down by shRNAs in T24 and J82 cell lines. While the migration of BC cells was not affected after the knockdown of CD81, the invasive activity was significantly increased in both cell lines. Zymography produced distinct bands using supernatants from CD81-knockdown cells, whereas only faint bands were observed with empty vector-transfected cells. We also observed an increased expression of MMPs, specifically MMP2 and 9, in the conditioned media from CD81-knockdown cells by western blotting. Mechanistically, the phosphorylation of extracellular signal-regulated kinase (ERK) was associated with the invasive activity of BC cells, while U0126 (an ERK inhibitor) reduced the invasive activity of CD81-knockdown BC cells.

Conclusions: Taken together, CD81 suppression promotes the invasive property of BC cells through MMP signaling via ERK phosphorylation. Our results suggest that the regulation of CD81 expression may have some therapeutic potential in BC.

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References

Lee M, Kim J, Lee J, Yun S, Kim W, Ahn H . Prognostic Significance of CREB-Binding Protein and CD81 Expression in Primary High Grade Non-Muscle Invasive Bladder Cancer: Identification of Novel Biomarkers for Bladder Cancer Using Antibody Microarray. PLoS One. 2015; 10(4):e0125405. PMC: 4411067. DOI: 10.1371/journal.pone.0125405. View

Miyake M, Fujimoto K, Hirao Y . Active surveillance for nonmuscle invasive bladder cancer. Investig Clin Urol. 2016; 57 Suppl 1:S4-S13. PMC: 4910757. DOI: 10.4111/icu.2016.57.S1.S4. View

Hong I, Byun H, Lee J, Jin Y, Wang S, Jeoung D . The tetraspanin CD81 protein increases melanoma cell motility by up-regulating metalloproteinase MT1-MMP expression through the pro-oncogenic Akt-dependent Sp1 activation signaling pathways. J Biol Chem. 2014; 289(22):15691-704. PMC: 4140923. DOI: 10.1074/jbc.M113.534206. View

Kanayama H, Yokota K, Kurokawa Y, Murakami Y, Nishitani M, Kagawa S . Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer. Cancer. 1998; 82(7):1359-66. View

Verma R, Hansch C . Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem. 2007; 15(6):2223-68. DOI: 10.1016/j.bmc.2007.01.011. View

van Rhijn B, Burger M, Lotan Y, Solsona E, Stief C, Sylvester R . Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009; 56(3):430-42. DOI: 10.1016/j.eururo.2009.06.028. View

Craig Hall M, Chang S, Dalbagni G, Pruthi R, Seigne J, Skinner E . Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol. 2007; 178(6):2314-30. DOI: 10.1016/j.juro.2007.09.003. View

Levy S, Todd S, Maecker H . CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu Rev Immunol. 1998; 16:89-109. DOI: 10.1146/annurev.immunol.16.1.89. View

Sun Y, Liu W, Liu T, Feng X, Yang N, Zhou H . Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 2015; 35(6):600-4. DOI: 10.3109/10799893.2015.1030412. View

10.

Carloni V, Mazzocca A, Ravichandran K . Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene. 2003; 23(8):1566-74. DOI: 10.1038/sj.onc.1207287. View

11.

Lafleur M, Xu D, Hemler M . Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis. Mol Biol Cell. 2009; 20(7):2030-40. PMC: 2663921. DOI: 10.1091/mbc.e08-11-1149. View

12.

Mazzocca A, Liotta F, Carloni V . Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma. Gastroenterology. 2008; 135(1):244-256.e1. DOI: 10.1053/j.gastro.2008.03.024. View

13.

White A, Lamb P, Barrett J . Frequent downregulation of the KAI1(CD82) metastasis suppressor protein in human cancer cell lines. Oncogene. 1998; 16(24):3143-9. DOI: 10.1038/sj.onc.1201852. View

14.

Davies B, Waxman J, Wasan H, Abel P, Williams G, Krausz T . Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res. 1993; 53(22):5365-9. View

15.

Vences-Catalan F, Rajapaksa R, Srivastava M, Marabelle A, Kuo C, Levy R . Tetraspanin CD81 promotes tumor growth and metastasis by modulating the functions of T regulatory and myeloid-derived suppressor cells. Cancer Res. 2015; 75(21):4517-26. DOI: 10.1158/0008-5472.CAN-15-1021. View

16.

Vences-Catalan F, Rajapaksa R, Srivastava M, Marabelle A, Kuo C, Levy R . Tetraspanin CD81, a modulator of immune suppression in cancer and metastasis. Oncoimmunology. 2016; 5(5):e1120399. PMC: 4910756. DOI: 10.1080/2162402X.2015.1120399. View

17.

Zhang N, Zuo L, Zheng H, Li G, Hu X . Increased Expression of CD81 in Breast Cancer Tissue is Associated with Reduced Patient Prognosis and Increased Cell Migration and Proliferation in MDA-MB-231 and MDA-MB-435S Human Breast Cancer Cell Lines In Vitro. Med Sci Monit. 2018; 24:5739-5747. PMC: 6109364. DOI: 10.12659/MSM.911612. View

18.

Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J . EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2008; 54(2):303-14. DOI: 10.1016/j.eururo.2008.04.051. View

19.

Van Lint P, Libert C . Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol. 2007; 82(6):1375-81. DOI: 10.1189/jlb.0607338. View

20.

Vences-Catalan F, Duault C, Kuo C, Rajapaksa R, Levy R, Levy S . CD81 as a tumor target. Biochem Soc Trans. 2017; 45(2):531-535. DOI: 10.1042/BST20160478. View