CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior
详细信息 查看全文
- 作者：Marina Poettler (5)
Matthias Unseld (5)
Kira Braemswig (5)
Andrea Haitel (6)
Christoph C Zielinski (5)
Gerald W Prager (5) - 关键词：Integrin ; Renal cell cancer ; CD98
- 刊名：Molecular Cancer
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：12
- 期：1
- 全文大小：785 KB
- 参考文献：1. Rini BI, / et al.: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. / Lancet 2011,378(9807):1931-939. CrossRef
2. Turnbull JD, Cobert J, Jaffe T, Harrison MR, George DJ, Armstrong AJ: Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors. / Clin Genitourin Cancer 2013, 11:45-0. CrossRef
3. Beuselinck B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, / et al.: Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. / Br J Cancer 2012, 107:1665-671. CrossRef
4. Mulders PF: Renal cell carcinoma. / World J Urol 2008, 26:113. CrossRef
5. Rini BI, Rathmell WK, Godley P: Renal cell carcinoma. / Curr Opin Oncol 2008, 20:300-06. CrossRef
6. Prager GW, Poettler M, Schmidinger M, Mazal PR, Susani M, Zielinski CC, / et al.: CD98hc (SLC3A2), a novel marker in renal cell cancer. / Eur J Clin Invest 2009, 39:304-10. CrossRef
7. Feral CC, Nishiya N, Fenczik CA, Stuhlmann H, Slepak M, Ginsberg MH: CD98hc (SLC3A2) mediates integrin signaling. / Proc Natl Acad Sci USA 2005,102(2):355-60. CrossRef
8. Tsumura H, Suzuki N, Saito H, Kawano M, Otake S, Kozuka Y, / et al.: The targeted disruption of the CD98 gene results in embryonic lethality. / Biochem Biophys Res Commun 2003, 308:847-51. CrossRef
9. Henderson NC, Collis EA, Mackinnon AC, Simpson KJ, Haslett C, Zent R, / et al.: CD98hc (SLC3A2) interaction with beta 1 integrins is required for transformation. / J Biol Chem 2004, 279:54731-4741. CrossRef
10. Rintoul RC, Buttery RC, Mackinnon AC, Wong WS, Mosher D, Haslett C, / et al.: Cross-linking CD98 promotes integrin-like signaling and anchorage-independent growth. / Mol Biol Cell 2002, 13:2841-852. CrossRef
11. Fenczik CA, Sethi T, Ramos JW, Hughes PE, Ginsberg MH: Complementation of dominant suppression implicates CD98 in integrin activation. / Nature 1997, 390:81-5. CrossRef
12. Zent R, Fenczik CA, Calderwood DA, Liu S, Dellos M, Ginsberg MH: Class- and splice variant-specific association of CD98 with integrin beta cytoplasmic domains. / J Biol Chem 2000, 275:5059-064. CrossRef
13. Merlin D, Sitaraman S, Liu X, Eastburn K, Sun J, Kucharzik T, / et al.: CD98-mediated links between amino acid transport and beta 1 integrin distribution in polarized columnar epithelia. / J Biol Chem 2001, 276:39282-9289. CrossRef
14. Miyamoto YJ, Mitchell JS, McIntyre BW: Physical association and functional interaction between beta1 integrin and CD98 on human T lymphocytes. / Mol Immunol 2003, 39:739-51. CrossRef
15. Stroeken PJ, van Rijthoven EA, Boer E, Geerts D, Roos E: Cytoplasmic domain mutants of beta1 integrin, expressed in beta 1-knockout lymphoma cells, have distinct effects on adhesion, invasion and metastasis. / Oncogene 2000, 19:1232-238. CrossRef
16. Filardo EJ, Brooks PC, Deming SL, Damsky C, Cheresh DA: Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. / J Cell Biol 1995, 130:441-50. CrossRef
17. Parsons M, Keppler MD, Kline A, Messent A, Humphries MJ, Gilchrist R, / et al.: Site-directed perturbation of protein kinase C-integrin interaction blocks carcinoma cell chemotaxis. / Mol Cell Biol 2002, 22:5897-911. CrossRef
18. Prager GW, Feral CC, Kim C, Han J, Ginsberg MH: CD98hc (SLC3A2) Interaction with the Integrin beta Subunit Cytoplasmic Domain Mediates Adhesive Signaling. / J Biol Chem 2007, 282:24477-4484. CrossRef
19. Haynes BF, Hemler ME, Mann DL, Eisenbarth GS, Shelhamer J, Mostowski HS, / et al.: Characterization of a monoclonal antibody (4?F2) that binds to human monocytes and to a subset of activated lymphocytes. / J Immunol 1981, 126:1409-414.
20. Fenczik CA, Zent R, Dellos M, Calderwood DA, Satriano J, Kelly C, / et al.: Distinct domains of CD98hc regulate integrins and amino acid transport. / J Biol Chem 2001, 276:8746-752. CrossRef
21. Fogelstrand P, Feral CC, Zargham R, Ginsberg MH: Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2). / J Exp Med 2009, 206:2397-406. CrossRef
22. Boulter E, Estrach S, Errante A, Pons C, Cailleteau L, Tissot F, / et al.: CD98hc (SLC3A2) regulation of skin homeostasis wanes with age. / J Exp Med 2013, 210:173-90. CrossRef
23. Price LS, Leng J, Schwartz MA, Bokoch GM: Activation of Rac and Cdc42 by integrins mediates cell spreading. / Mol Biol Cell 1998, 9:1863-871. CrossRef
24. Cai S, Bulus N, Fonseca-Siesser PM, Chen D, Hanks SK, Pozzi A, / et al.: CD98 modulates integrin beta1 function in polarized epithelial cells. / J Cell Sci 2005, 118:889-99. CrossRef
25. Pear WS, Nolan GP, Scott ML, Baltimore D: Production of high-titer helper-free retroviruses by transient transfection. / Proc Natl Acad Sci USA 1993, 90:8392-396. CrossRef
26. Liu S, Thomas SM, Woodside DG, Rose DM, Kiosses WB, Pfaff M, / et al.: Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. / Nature 1999, 402:676-81. CrossRef
27. Sobin LH, International Union Against Cancer: / TNM Classification of Malignant Tumors. 6th edition. New York: Wiley; 2002:180-83.
28. Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. / Am J Surg Pathol 1982, 6:655-63. CrossRef - 作者单位：Marina Poettler (5)
Matthias Unseld (5)
Kira Braemswig (5)
Andrea Haitel (6)
Christoph C Zielinski (5)
Gerald W Prager (5)
5. Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
6. Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria - ISSN：1476-4598
文摘
Background Overexpression of CD98hc (SLC3A2) occurs in a variety of cancers and is suspected to contribute to tumor growth. CD98, a heterodimeric transmembrane protein, physically associates with certain integrin β subunit cytoplasmic domains via its heavy chain, CD98hc. CD98hc regulates adhesion-induced intracellular signal transduction via integrins, thereby, affecting cell proliferation and clonal expansion. Disruption of CD98hc led to embryonic lethality in mice (E 3.5 and E 9.5) and CD98hc ??embryonic stem cell transplantation failed to form teratomas, while CD98hc over-expression in somatic cells resulted in anchorage-independent growth. However, it is unclear whether interference with CD98hc expression tumor cell behavior. Methods Renal cell cancer cell lines have been used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometric analysis was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to stably knockdown or reconstitute full length or mutated CD98hc. The role of CD98 as a promotor of tumorigenesis was evaluated using an in in vivo tumor transplantation animal model. Immunohistochemical analysis was performed to analyze cell proliferation and CD98 expression in tumors. Results This report shows that CD98hc silencing in clear cell renal cancer cells reverts certain characteristics of tumorigenesis, including cell spreading, migration, proliferation and survival in vitro, and tumor growth in vivo. Acquisition of tumorigenic characteristics in clear cell renal cancer cells occurred through the integrin binding domain of CD98hc. A CD98hc/integrin interaction was required for adhesion-induced sustained FAK phosphorylation and activation of the major downstream signaling pathways PI3k/Akt and MEK/ERK, while overexpression of a constitutive active form of FAK rescued the CD98hc deficiency. Conclusions In this study we demonstrate that loss of CD98hc blocks tumorigenic potential in renal cell cancer.