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Short-term induction and long-term suppression of HPV16 oncogene silencing by RNA interference in cervical cancer

S Tang1, M Tao, J P McCoy

  • 1HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1868, USA.

Oncogene
|December 22, 2005
PubMed

Insights

Potent small interfering RNA (siRNA) targeting human papillomavirus 16 (HPV16) oncogenes lost function over time in cell culture. Cells developed a suppressive mechanism involving a cytoplasmic protein that interfered with siRNA activity.

Area of Science:

  • Molecular Biology
  • Virology
  • Gene Regulation

Background:

  • RNA interference (RNAi) is a powerful tool for gene silencing.
  • Small interfering RNA (siRNA) can suppress gene expression by targeting specific RNA sequences.

Purpose of the Study:

  • To investigate the long-term efficacy and potential resistance mechanisms of siRNA targeting human papillomavirus 16 (HPV16) oncogenes.
  • To understand how siRNA gene silencing function is maintained or lost in cancer cells.

Main Methods:

  • Developed and stably expressed short hairpin RNA (shRNA) targeting HPV16 E6E7 oncogenes in HPV16+ cancer cells (CaSki and SiHa).
  • Assessed siRNA silencing efficiency across different cell passages.
  • Analyzed siRNA processing, RNA-induced silencing complex (RISC) formation, and protein interactions in resistant cells.

Main Results:

  • siRNA-mediated silencing of HPV16 E6 and E7 oncogenes was potent initially but became inefficient with increased cell passages.
  • Loss of siRNA function was gene-selective and occurred after initial siRNA processing steps.
  • siRNA-resistant cells uniquely expressed a ~50 kDa cytoplasmic protein that specifically interacted with the antisense strand of the E7 siRNA.

Conclusions:

  • Potent siRNA targeting essential or regulatory genes can induce cellular mechanisms to suppress siRNA function.
  • This suggests a potential cellular defense against highly effective gene silencing strategies.
  • Further research is needed to elucidate the precise mechanism of this siRNA suppressive function.

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