Human papillomavirus types 16 E6 and E7 contribute differently to carcinogenesis.
High-risk human papillomaviruses (HPVs) are etiologically implicated in human cervical cancer. Two viral genes, E6 and E7, are commonly found expressed in these cancer cells. We have previously shown that mice transgenic for the HPV-16 E6 gene or E7 gene, in which the E6 or E7 was expressed in the basal layer of epithelia, developed skin tumors. The spectrum of tumors derived from E6 and E7 mice differed, however; although most tumors derived from the E7-transgenic mice were benign, the majority of the tumors from the E6-transgenic mice were malignant. These findings led us to hypothesize that E6 and E7 play different roles in carcinogenesis. To assess at what stages in carcinogenesis E6 and E7 act, we treated the skin of K14E6- and K14E7-transgenic mice with chemical carcinogens known to contribute to distinct stages in carcinogenesis. Both E6 and E7 were found to synergize with chemical carcinogens in causing tumor formation. E6 was found to act weakly at the promotion stage of carcinogenesis in the formation of benign tumors but strongly at the progression stage which involves the malignant conversion of benign tumors. In contrast, E7 primarily affected the promotion stage of carcinogenesis. These results provide direct evidence that E6 and E7 contribute differently to carcinogenesis; E7 promotes the formation of benign tumors, and E6 acts primarily to accelerate progression of these benign tumors to the malignant stage. Consistent with this model, we found E6 and E7 to cooperate in inducing tumor formation in mice expressing both oncogenes.
Song
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McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, Wisconsin 53706, USA.
Liem
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Miller
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Lambert
P F
PF
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects*; D003043:Cocarcinogenesis; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D010212:Papilloma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D012720:Severity of Illness Index; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects
D002273:Carcinogens; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate