High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancer, the second most common cause of cancer death in women worldwide. HPVs are also associated with a number of other anogenital tract carcinomas, including anal, vulvar and penile cancers, as well as approximately 20% of oral cancers, particularly oropharyngeal carcinomas. Despite the recently introduced prophylactic vaccine, which prevents new high-risk HPV infections, the long latency period between the initial HPV infection and cancer development predicts it will be decades before a significant impact on the incidence and mortality of HPV associated cancers is made. Until then, 10 women will die of HPV-associated cervical cancer every day in the US, alone. HPV-associated carcinogenesis is driven by viral E6/E7 oncoprotein expression. These proteins not only contribute to induction of premalignant lesions, but also mechanistically contribute to malignant progression. We have shown that the HPV E7 oncoprotein induces the expression of a host, cellular microRNA-34a (miR-34a). miR-34a has potent tumor suppressor activity and is a direct transcriptional target of p53. However, it is clear that other regulators of miR-34a exist, given p53-independent upregulation of miR-34a has been observed. E7 enhances miR-34a expression through a mechanism independent of p53. The induction of miR-34a by E7 may represent an innate, cellular defense mechanism mounted by the cell in response to an "oncogenic hit." Alternatively, E7 may induce expression of this miR to mediate critical biological activities during the viral lifecycle. This project is focused on investigating mechanisms and biological consequences of HPV16 E7 induction of miR-34a. Aim 1 is to determine the mechanism of induction of miR- 34a by E7 expression. Aim 2 is to evaluate the involvement of miR-34a in modulation of E7-induced senescence. Lastly, aim 3 is to address the role of miR-34a in the HPV16 lifecycle. Through studying this miR, a greater understanding of how HPVs cause cancer will be elucidated.
