Cervical cancer is the leading cause of cancer-specific mortality amongst women worldwide and the human papilloma virus (HPV) plays a pathophysiologic role in cervical carcinogenesis in over 95% of cases. For over half a century, it has become increasingly established that intratumoral hypoxia is associated with an aggressive clinical phenotype, manifested by resistance to radiation and chemotherapy, a high risk of recurrence and metastasis, and shortened overall survival. The mechanistic underpinnings that account for these adverse clinical sequelae of hypoxia have not been elucidated. We recently identified a biochemical link between HPV infection and hypoxia in cervical cancer (Cancer Cell, 14:394, 2008). Specifically, we found that the HPV-encoded E6 protein mediates prolonged activation of the NF kappa B (NF-:B) signaling pathway under hypoxic conditions. As oxygen becomes a limiting substrate, E6 effectively targets CYLD, a negative regulator of the NF-:B pathway, for proteasome-mediated degradation, and thereby allows for unrestricted NF-:B activation. Through its transcriptional activity, NF-:B drives proliferation, survival, neo-angiogenesis, invasion and metastasis. Thus, we postulate that the poor clinical outcomes associated with hypoxia can in large part be attributed to E6-mediated, hypoxia-induced NF- :B activation. In pursuit of our hypothesis, we propose three aims in which we will be: 1) elucidating some of the key remaining biochemical and molecular cues that drive the E6-CYLD interaction (Specific Aim 1), 2) examining the relative effects of hypoxia-induced versus constitutive NF-:B activation on cervical tumorigenesis and metastasis development in murine xenografts models (Specific Aim 2), and 3) prospectively studying the relationship between hypoxia and NF-:B activation and CYLD expression in tumors of cervical cancer patients (Specific Aim 3). We have assembled a team of physician-scientists with diverse skill sets from various disciplines, including medical oncology, gynecologic oncology, and gynecologic pathology to further our molecular understanding of the hypoxic phenotype. Accomplishments from this proposal represent a necessary prelude to translate our work to early phase clinical trials aimed at targeting hypoxia-induced NF-:B activation, which can take advantage of the potentially high therapeutic index afforded by HPV positivity.
(Relevance to Veterans'Health) With the recent expansion of women in the military, 14% of active duty forces and 20% of new military recruits are female. The number of female veterans, estimated currently at two million, is expected to increase by 10% by the year 2010. Accordingly, research endeavors targeting women's health issues, including gender- specific malignancies such as cervical cancer, are highly relevant to the mission of the VA. Moreover, our proposed research on the role of the HPV-encoded E6 protein in cervical oncogenesis will have relevance to and share potential scientific impact on other HPV-associated malignancies, including cancers of the oropharynx, anus, penis, vulva and others, thereby further broadening the relevance of our line of research to diseases that affect large cohorts of male and female veterans alike.