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Overexpression of p16INK4a as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia
  1. M. Ishikawa*,
  2. T. Fujii*,
  3. M. Saito*,
  4. I. Nindl,
  5. A. Ono*,
  6. K. Kubushiro*,
  7. K. Tsukazaki*,
  8. M. Mukai* and
  9. S. Nozawa*
  1. *Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  2. Charité, Klinik für Dermatologie, Venerologie und Allergologie, Immundermatologie, Berlin, Germany
  1. Address correspondence and reprint requests to: Takuma Fujii, Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: fujiit{at}


Overexpression of p16INK4a has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16INK4a and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16INK4a overexpression was investigated immunohistochemically using a p16INK4a-specific monoclonal antibody (clone E6H4). In high–risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16INK4a overexpression. The incidence of p16INK4a overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16INK4a overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16INK4a as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.

  • cervical squamous neoplasia
  • HPV
  • p16INK4a

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