Title: TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma.

Authors: Hall, Daniel P; Cost, Nicholas G; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R; Meller, Jarek; Czyzyk-Krzeska, Maria F

Published In Cancer Cell, (2014 Nov 10)

Abstract: Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).

PubMed ID: 25517751

MeSH Terms: Animals; Autophagy*; Carcinoma, Renal Cell/genetics; Carcinoma, Renal Cell/metabolism; Carcinoma, Renal Cell/pathology*; Caveolin 1/metabolism; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Kidney Neoplasms/genetics; Kidney Neoplasms/pathology*; Mice, Nude; MicroRNAs/physiology*; Neoplasm Transplantation; Oncogenes; RNA Interference; TRPM Cation Channels/genetics*; TRPM Cation Channels/metabolism; Tumor Burden; Von Hippel-Lindau Tumor Suppressor Protein/metabolism