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Cervical cancer ranks as the most common female cancer in the developing world with an estimated global incidence of 470,000 cases per year and approximately 233,000 deaths. Incidence becomes significantly lower in developed countries as a consequence of cervical screening to identify women at highest risk and of ongoing active health education programs. Cervical cancer is the third most common type of cancer in the U.S. with an estimated 40,880 new cases in 2005, and is the eighth leading cause of cancer mortality, accounting for an estimated 7,310 deaths in 2005. Sexual transmission and infection with human papillomaviruses (HPVs) is widely recognized as a cause of cervical cancer. The causal relationship between high-risk HPV (HR-HPV) infection and cervical cancer has been well documented from epidemiological and functional studies. HR-HPVs, such as HPV16, HPV18, and HPV31, have been detected in up to 99.7% of cervical squamous cell carcinomas and 94-100% of cervical adeno- and adenosquamous carcinomas. It has been also documented that women with HIV infection have a high prevalence of cervical HPV infection and cervical cancer has been the most common malignancy among women with AIDS in both the U.S. and Europe. Although both HIV and HPV are sexually transmitted and this could partly account for the higher prevalence of HPV infection in HIV+ patients, HIV-associated immunosuppression might contribute to reactivation of pre-existing HPV infection and predispose to progression to high-grade squamous intraepithelial lesions.
The infection through sexual intercourse is initiated when a viral particle gains entry into a basal epithelial cell of the cervix. Viral gene expression and multiplication occur exclusively in the nuclei of the infected cells, and are tightly linked to the state of differentiation of the cells. Two viral oncoproteins, E6 and E7, of HR-HPVs are involved in cervical carcinogenesis and respectively, inactivate cellular tumor suppressor proteins p53 and pRb. Two oncogenes express their oncoproteins during early virus infection and more prominent in cervical cancer cells. However, HR-HPV E6 and E7 are transcribed from the same promoter as a single bicistronic RNA in HPV-positive cervical cancer and its derived cell lines, raising some questions on how each oncoprotein could be produced. Currently, my lab is focusing on (1) post-transcriptional control of both E6 and E7 expression in understanding mechanism(s) that regulate both E6 and E7 expression from the bicistronic RNA, (2) seeking an RNA-based gene therapy to eliminate E6 and E7 expression for treatment of cervical cancer, (3) determining roles and functions of microRNAs in oncogenesis and HPV infection of cervical cancer, (4) exploring new molecular markers for early diagnosis of cervical cancer.
