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Critical role for D-type cyclins in cellular transformation induced by E6/E7 of human papillomavirus type 16 and

Amber Yasmeen1, Abdel N Hosein, Qunyan Yu

  • 1Program in Cancer Genetics, The Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, McGill University Montreal, QC H3T1E2, Canada.

Cancer Science
|May 11, 2007
PubMed

Insights

Human papillomavirus (HPV) E6/E7 oncoproteins and ErbB-2 receptor cooperate to transform cells. Cyclins D1, D2, and D3 are crucial mediators of this transformation, suggesting potential therapeutic targets for HPV-related cancers.

Area of Science:

  • Oncology
  • Cell Biology
  • Virology

Background:

  • Human papillomavirus (HPV) type 16 E6/E7 oncoproteins can induce cellular transformation.
  • ErbB-2 receptor tyrosine kinase is implicated in various cancers.
  • Previous studies showed HPV E6/E7 cooperates with ErbB-2 to transform cells, with cyclin D1 being essential.

Purpose of the Study:

  • To investigate the roles of all D-type cyclins (D1, D2, and D3) in cellular transformation induced by HPV E6/E7 and ErbB-2.
  • To determine the necessity of D-type cyclins for E6/E7/ErbB-2-mediated neoplastic transformation in vitro and in vivo.

Main Methods:

  • Utilized mouse normal embryonic fibroblast (NEF) cells and human normal oral epithelial (NOE) cells.
  • Generated and employed NEF cells deficient in cyclin D1, D2, or D3 (NEF-D1(-/-), NEF-D2(-/-), NEF-D3(-/-)).
  • Assessed cellular transformation through soft agar colony formation assays and tumor formation in nude mice.
  • Used small interfering RNA (siRNA) to inhibit cyclin D2 and D3 expression in transformed cell lines.

Main Results:

  • HPV E6/E7 and E6/E7/ErbB-2, but not ErbB-2 alone, induced transformation in wild-type NEF cells.
  • Neoplastic transformation was abrogated in cyclin D1 and D2 knockout cells.
  • Cyclin D3 deficiency partially reduced transformation, while E6/E7/ErbB-2 cooperation was required for transformation in D3(-/-) cells.
  • siRNA-mediated knockdown of cyclin D2 and D3 partially inhibited colony and tumor formation in transformed cell lines.

Conclusions:

  • Cyclins D1 and D2 are essential for E6/E7/ErbB-2-mediated cellular transformation.
  • Cyclin D3 plays a supporting role in this transformation process.
  • These findings highlight the critical role of D-type cyclins in HPV-driven oncogenesis and suggest their potential as therapeutic targets for HPV-associated cancers.

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