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MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer

M V Geraldo1, A S Yamashita, E T Kimura

  • 1Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Oncogene
|August 30, 2011
PubMed

Insights

MicroRNA-146b-5p promotes papillary thyroid cancer by inhibiting SMAD4 and disrupting the TGF-β pathway. Suppressing this microRNA reduces cancer cell proliferation and restores TGF-β signaling.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • MicroRNAs (miRNAs) are key regulators of gene expression implicated in various cancers, including papillary thyroid carcinoma (PTC).
  • miR-146b-5p is overexpressed in PTC and serves as a diagnostic marker.
  • The transforming growth factor β (TGF-β) pathway normally inhibits thyroid follicular cell growth, but its evasion mechanism in cancer is unclear.

Purpose of the Study:

  • To investigate the role of miR-146b-5p in papillary thyroid carcinoma.
  • To determine if miR-146b-5p modulates the TGF-β signaling pathway.
  • To elucidate the contribution of miR-146b-5p to thyroid tumorigenesis.

Main Methods:

  • Computational analysis to predict miR-146b-5p binding to SMAD4 3'UTR.
  • Luciferase reporter assays to confirm direct binding.
  • Inhibition of miR-146b-5p in human PTC cell lines (TPC-1, BCPAP) and overexpression in normal rat follicular cells (PCCL3).
  • Assessment of SMAD4 levels, TGF-β pathway response, cell proliferation, and cell-cycle arrest.

Main Results:

  • miR-146b-5p directly binds to the SMAD4 3'UTR.
  • Inhibiting miR-146b-5p increased SMAD4 levels and restored TGF-β anti-proliferative effects in PTC cells.
  • Overexpressing miR-146b-5p in normal cells decreased SMAD4, disrupted TGF-β signaling, increased proliferation, and conferred resistance to TGF-β-induced cell-cycle arrest.
  • Oncogenic RET/PTC3 and BRAF activation upregulated miR-146b-5p expression.

Conclusions:

  • miR-146b-5p exhibits an oncogenic role in thyroid follicular cells.
  • miR-146b-5p contributes to thyroid tumorigenesis by inhibiting SMAD4 and impairing TGF-β pathway function.
  • This study clarifies a mechanism by which cancer cells evade TGF-β signaling.

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