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

Cancer Cell. 2014 Nov 10;26(5):738-53. doi: 10.1016/j.ccell.2014.09.015. Epub 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).

Publication types

  • Research Support, N.I.H., Extramural

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

Substances

  • CAV1 protein, human
  • Caveolin 1
  • MIRN204 microRNA, human
  • MicroRNAs
  • TRPM Cation Channels
  • TRPM3 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human