[Molecular basis of cervical carcinogenesis by high-risk human papillomaviruses].
Over the last two decades since discovery of human papillomavirus (HPV) type 16 and 18 DNAs in cervical cancers by Dr. Harald zur Hausen, HPVs have been well characterized as causative agents for cervical cancer. Viral DNA from a specific group of HPVs can be detected in at least 90% of all cervical cancers and two viral genes, E6 and E7, are invariably expressed in HPV-positive cervical cancer cells. Their gene products are known to inactivate the major tumor suppressors, p53 and pRB, respectively. In addition, one function of E6 is to activate telomerase, and E6 and E7 cooperate to effectively immortalize human primary epithelial cells. Though expression of E6 and E7 is itself not sufficient for cancer development, it seems to be either directly or indirectly involved in every stage of multi-step carcinogenesis. Indeed, it has been shown that only one or two genetic alterations in addition to expression of E6 and E7 are experimentally sufficient to confer tumorigenicity to normal human cervical keratinocytes. Epidemiological and biological studies suggest the potential efficacy of prophylactic vaccines to prevent genital HPV infection as an anti-cancer strategy. However, given the widespread nature of HPV infection and unresolved issues about the duration and type specificity of the currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of the viral oncoproteins be elucidated in order to provide the basis for development of new therapeutic strategies against HPV-associated malignancies. This review highlights the novel functions of E6 and E7 as well as the molecular mechanisms of HPV-induced carcinogenesis.
Virology Division, National Cancer Center Research Institute. tyugawa@ncc.go.jp
Takashi
T
Yugawa
Tohru
T
Kiyono
D005260:Female; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000502:physiology; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000235:genetics* / Q000517:prevention & control / Q000821:virology*; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins / Q000502:physiology; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000517:prevention & control / Q000821:virology*
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16