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Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell

Mohammad Iqbal Rather1, Mathighatta N Nagashri, Shivananda S Swamy

  • 1Department of Molecular Reproduction, Indian Institute of Science, Bangalore 560012, India.

The Journal of Biological Chemistry
|November 21, 2012
PubMed

Insights

Oral squamous cell carcinoma (OSCC) shows down-regulated CDC73, driven by oncogenic microRNA-155 (miR-155). Restoring CDC73 levels using an miR-155 antagonist may offer a novel therapeutic strategy for OSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The CDC73 gene is crucial in regulating cell growth and is inactivated in various cancers.
  • Down-regulation of CDC73 has been observed in several carcinomas, but its role in oral squamous cell carcinoma (OSCC) remains unclear.
  • MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in cancer development.

Purpose of the Study:

  • To investigate the role of CDC73 in OSCC.
  • To determine the mechanism of CDC73 down-regulation in OSCC, focusing on the potential involvement of microRNA-155 (miR-155).
  • To evaluate the therapeutic potential of targeting miR-155 in OSCC.

Main Methods:

  • Quantitative real-time PCR to assess CDC73 and miR-155 expression in OSCC samples and cell lines.
  • Luciferase reporter assays to confirm the direct interaction between miR-155 and CDC73.
  • In vitro experiments involving ectopic expression of miR-155 or delivery of an miR-155 antagonist (antagomir-155) in cancer cells.
  • Western blotting to analyze protein levels of CDC73, β-catenin, cyclin D1, and c-MYC.
  • Xenograft mouse models to assess the in vivo efficacy of antagomir-155 treatment.

Main Results:

  • CDC73 expression was significantly down-regulated in a majority of OSCC patient samples.
  • Oncogenic miR-155 was found to directly target and inhibit CDC73 expression in OSCC cells.
  • Overexpression of miR-155 promoted cell viability and inhibited apoptosis, while antagomir-155 treatment reversed these effects and led to tumor regression in vivo.
  • Restoration of CDC73 levels abrogated the pro-oncogenic effects of miR-155.

Conclusions:

  • miR-155-mediated down-regulation of CDC73 is a key mechanism contributing to OSCC development.
  • Targeting miR-155 with antagonists like antagomir-155 represents a promising therapeutic strategy for OSCC.
  • Restoring CDC73 expression holds potential for cancer therapy, particularly in miR-155-driven malignancies.

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