An in vitro multistep carcinogenesis model for human cervical cancer

Mako Narisawa-Saito, Yuki Yoshimatsu, Shin Ichi Ohno, Takashi Yugawa, Nagayasu Egawa, Masatoshi Fujita, Setsuo Hirohashi, Tohru Kiyono

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)


Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of E6 and E7 genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 E6 and E7 with or without hTERT into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic Hras G12V (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumor-initiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer.

Original languageEnglish
Pages (from-to)5699-5705
Number of pages7
JournalCancer Research
Issue number14
Publication statusPublished - Jul 15 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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