As with RNA viruses, several oncogenic DNA viruses that cause tumors in animals have been identified. Five DNA viruses—HPV, Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus-8 [HHV-8]), a polyoma virus called Merkel cell virus, and hepatitis B virus (HBV)—are of special interest because they are strongly associated with human cancer. KSHV and Kaposi sarcoma are discussed in Chapter 5. Merkel cell virus is associated with a particular cancer, Merkel cell carcinoma, that is too rare to merit further discussion. The others are presented here. We also briefly touch on the oncogenic effects of hepatitis C virus, an RNA virus, during our discussion of HBV, since both viruses share an association with chronic liver injury and liver cancer.
Scores of genetically distinct types of HPV have been identified. Some types (e.g., 1, 2, 4, and 7) cause benign squamous papillomas (warts) in humans (Chapters 18 and 24). Genital warts have low malignant potential and are also associated with low-risk HPVs, predominantly HPV-6 and HPV-11. By contrast, high-risk HPVs (e.g., types 16 and 18) cause several cancers, particularly squamous cell carcinoma of the cervix and anogenital region. In addition, at least 20% of oropharyngeal cancers, particularly those arising in the tonsils, are associated with high-risk HPVs.
The oncogenic potential of HPV can be related to products of two early viral genes, E6 and E7 (
Fig. 6.33 ), each of which has several activities that are pro-oncogenic.
Oncogenic activities of E6. The E6 protein binds to and mediates the degradation of p53, and also stimulates the expression of TERT, the catalytic subunit of telomerase, which you will recall contributes to the immortalization of cells. E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types, a property that is likely to contribute to oncogenesis.
Oncogenic activities of E7. The E7 protein has effects that complement those of E6, all of which are centered on http://ebooksmedicine.net speeding cells through the G1-S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. E7 also inactivates the CDK inhibitors p21 and p27, and binds and presumably activates cyclins E and A.
An additional factor that contributes to the oncogenic potential of HPVs is viral integration into the host genome. In benign warts, the HPV genome is maintained in a non-integrated episomal form, while in cancers, the HPV genome is randomly integrated into the host genome. Integration interrupts a negative regulatory region in the viral DNA, resulting in overexpression of the E6 and E7 oncoproteins. Furthermore, cells in which the viral genome has integrated show significantly more genomic instability, which may contribute to acquisition of pro-oncogenic mutations in host cancer genes.