Down regulation of RhoC by microRNA-138 results in de-activation of FAK, Src and Erk1/2 signaling pathway in head and neck squamous cell carcinoma

Oral Oncol. 2014 May;50(5):448-56. doi: 10.1016/j.oraloncology.2014.01.014. Epub 2014 Feb 22.

Abstract

Objective: RhoC a pro-metastatic oncogene is constitutively active in many head and neck squamous cell carcinomas. MicroRNA-138 which possesses a documented tumor suppressor function can bind to the 3'UTR of RhoC mRNA and inhibit its activity. We hypothesize that miR-138 can inhibit the function of RhoC and consequently the activation of downstream target molecules involve in the signaling cascade. For this reason we investigated the role of miR-138 in HNSCC.

Methods: In vitro studies were carried out to evaluate the role of miR-138 in HNSCC cell lines and in primary tumors obtained from HNSCC patients. Real time RT-PCR, Western blot, cell motility, invasion and colony formation assays were performed according to standard procedures.

Results: Data obtained by G-LISA and real time PCR shows an inverse correlation between RhoC expression and miR-138 in HNSCC cell lines. Additionally, we obtained a similar pattern of RhoC and miR-138 expression in primary tumors from HNSCC patients. Over expression of miR-138 in HNSCC lines showed down regulation of RhoC, as well as a decrease in cell motility, invasion colony and stress fiber formation. Furthermore, a significant down regulation was observed for FAK, Src and Erk(1/2) upon miR-138 overexpression.

Conclusion: These findings strongly suggest that the inhibition of RhoC can be achieved by over expressing miR-138, which further attenuates the downstream signaling cascade leading to cancer progression and survival. Moreover, this study for the first time shows that down regulation of FAK, Src and Erk(1/2) by miR-138 overexpression is due to inhibition of RhoC in HNSCC.

Keywords: Erk(1/2); FAK; Head and neck cancer; RhoC; Src; miR-138.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Down-Regulation*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Head and Neck Neoplasms / enzymology
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • MAP Kinase Signaling System
  • MicroRNAs / physiology*
  • Proto-Oncogene Proteins pp60(c-src)
  • Signal Transduction*
  • rho GTP-Binding Proteins / metabolism*
  • rhoC GTP-Binding Protein

Substances

  • 3' Untranslated Regions
  • MIRN138 microRNA, human
  • MicroRNAs
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins pp60(c-src)
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoC GTP-Binding Protein