Abstract
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.
Highlights
Cervical cancers are thought to arise from cervical lesions after long persistent infection with high-risk human papillomaviruses (HPV; ref. 1)
HCK1T-E was further transduced with several oncogenes (Akt, ErbB2, Hras, Myc, and Hras plus Myc), and expression of the individual transgenes was confirmed by Western blotting (Fig. 1A)
The aims of this study were to establish models to allow in vitro reconstruction of events leading to HPV16-mediated multistep carcinogenesis and to evaluate the effect of individual alterations in this process
Summary
Cervical cancers are thought to arise from cervical lesions after long persistent infection with high-risk human papillomaviruses (HPV; ref. 1). Mild and moderate dysplasia lesions show relatively low levels of E6 and E7 expression from episomally replicated viral genomes in the basal cell layer, whereas severe dysplasia and invasive cancer lesions often display high-level expression of E6 and E7 [2] with integration of viral DNA into the host cell genome whereby neoplastic development is believed to be initiated. Life-time risk for HPV infection is f80% for sexually active women [3], in most cases, infections resolve spontaneously due to effective immune responses, and ultimate development of cervical cancer is relatively rare. Integration of the viral DNA into the host genome causing deregulated expression of E6 and E7 in basal cells is considered to be a rare but one of the critical events for cervical carcinogenesis. Epidemiologic and experimental studies indicate that viral gene expression is not in itself sufficient to induce cervical cancer, and additional genetic and/or
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