MUC1 Drives the Progression and Chemoresistance of Clear Cell Renal Carcinomas

Simple Summary Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional systemic therapies and also to targeted therapies. Identifying the actors and deciphering the molecular mechanisms that lead to tumor progression and/or chemoresistance is an important step in developing new therapeutic strategies to cure ccRCC. In this context, we focused our attention on MUC1, a membrane-bound mucin, which is overexpressed in two-thirds of cancers and known to play a role in tumor progression, chemoresistance, and the establishment of an immunosuppressive microenvironment. In this study, we show that MUC1 overexpression increases the proliferation, invasion, and migration of ccRCC cells and is involved in mediating resistance to conventional and targeted therapies. Overall, our data suggest that MUC1 silencing may represent a potential therapeutic option for ccRCC.Abstract While the transmembrane glycoprotein mucin 1 (MUC1) is clustered at the apical borders of normal epithelial cells, with transformation and loss of polarity, MUC1 is found at high levels in the cytosol and is uniformly distributed over the entire surface of carcinoma cells, where it can promote tumor progression and adversely affects the response to therapy. Clear cell renal cell carcinoma (ccRCC), the main histotype of kidney cancer, is typically highly resistant to conventional and targeted therapies for reasons that remain largely unknown. In this context, we investigated whether MUC1 also plays a pivotal role in the cellular and molecular events driving ccRCC progression and chemoresistance. We showed, using loss- and gain-of-function approaches in ccRCC-derived cell lines, that MUC1 not only influences tumor progression but also induces a multi-drug-resistant profile reminiscent of the activation of ABC drug efflux transporters. Overall, our results suggest that targeting MUC1 may represent a novel therapeutic approach to limit ccRCC progression and improve drug sensitivity.