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MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance
Author(s) -
Sheng Yonghua,
Ng Choa Ping,
Lourie Rohan,
Shah Esha T.,
He Yaowu,
Wong Kuan Yau,
Seim Inge,
Oancea Iulia,
Morais Christudas,
Jeffery Penny L.,
Hooper John,
Gobe Glenda C.,
McGuckin Michael A.
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30651
Subject(s) - cancer research , clear cell renal cell carcinoma , survivin , sunitinib , cancer , tumor progression , sorafenib , angiogenesis , biology , cyclin d1 , cell growth , carcinogenesis , gene silencing , cell cycle , tyrosine kinase , cancer cell , medicine , renal cell carcinoma , receptor , biochemistry , genetics , hepatocellular carcinoma , gene
Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti‐apoptotic proteins, BCL‐xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi‐kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.