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microRNA-21 governs TORC1 activation in renal cancer cell proliferation and invasion

Nirmalya Dey1, Falguni Das, Nandini Ghosh-Choudhury

  • 1Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.

Plos One
|June 12, 2012
PubMed

Insights

MicroRNA-21 (miR-21) drives renal cancer cell proliferation and invasion by suppressing PTEN and activating the Akt/TORC1 pathway. Inhibiting miR-21 function halts cancer cell growth and migration.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Metastatic renal cancer exhibits distinct gene expression profiles.
  • MicroRNAs (miRNAs) are implicated in human cancers, with miR-21 suggested to play a role in renal cell carcinoma.
  • The functional role of miR-21 in renal cancer cell proliferation and invasion remains uncharacterized.

Purpose of the Study:

  • To investigate the functional role of miR-21 in renal cancer cell proliferation and invasion.
  • To elucidate the molecular mechanisms by which miR-21 influences renal cancer progression.
  • To identify potential therapeutic targets for renal cancer treatment.

Main Methods:

  • Cultured renal carcinoma cells and normal proximal tubular epithelial cells were used for comparative analysis.
  • Quantitative real-time PCR was employed to assess miR-21 expression levels.
  • miR-21 Sponge constructs were utilized to inhibit endogenous miR-21 activity.
  • Western blotting was performed to evaluate protein levels of PTEN, Akt, tuberin, and TORC1.
  • Functional assays assessed cell proliferation, migration, and invasion.

Main Results:

  • Mature, pre-, and pri-miR-21 levels were significantly upregulated in renal cancer cells due to increased transcription.
  • Overexpression of miR-21 Sponge inhibited renal cancer cell proliferation, migration, and invasion.
  • miR-21 directly targets PTEN mRNA, leading to decreased PTEN protein expression and increased Akt phosphorylation.
  • PTEN downregulation or constitutively active Akt abrogated miR-21 Sponge-mediated inhibition of cell proliferation and migration.
  • miR-21 Sponge inhibited tuberin phosphorylation and TORC1 activation, effects that were counteracted by constitutively active TORC1.

Conclusions:

  • Transcriptional activation of miR-21 drives renal cancer cell proliferation and invasion.
  • miR-21 promotes oncogenesis by post-transcriptionally downregulating PTEN, thereby activating the Akt/TORC1 signaling pathway.
  • Targeting miR-21 or the downstream Akt/TORC1 pathway represents a potential therapeutic strategy for metastatic renal cancer.

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