Human Papillomavirus-Related Diseases of the Female Lower Genital Tract: Oncogenic Aspects and Molecular Interaction

Joško Zekan, Mihael Skerlev, Lukrecija Milić, Deni Karelović

Abstract


The causal role of human papilloma virus (HPV) in all cancer of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of the vulva and vagina are also induced by HPV. Papillomaviruses are perfectly adapted to their natural host tissue, the differentiating epithelial cell of skin or mucosae and exploit the cellular machinery for their own purposes. The infectious cycle is initiated when infectious particles reach the basal layer of the epithelium, where they bind to and enter into cells. The critical molecules in the process of virus replication are the viral proteins E6 and E7, which interact with a number of cellular proteins. In experimental system these interactions have been show to induce proliferation and eventually immortalization and malignant transformation of cells. Binding of E7 to pRb activates the E2F transcription factor, which triggers the expression of proteins necessary for DNA replication. Unscheduled S-phase would normally lead to apoptosis by the action of p53. However, in HPV-infected cells, this process is counteracted by the viral E6 protein, which targets p53 for proteolytic degradation. Besides blocking p53 function in regulation of apoptosis, high-risk HPV proteins interact with both extrinsic and intrinsic apoptotic pathways. As an aberration of virus infection, constant activity of the viral proteins E6 and E7 leads to increasing genomic instability, accumulation of oncogene mutations, further loss of cell-growth control and ultimately cancer. The immune system uses innate and adaptive immunity to recognize and combat foreign agents that invade the body, but these methods are sometimes ineffective against human papillomavirus. HPV has several mechanisms for avoiding the immune system. Furthermore, HPV infections disrupt cytokine expression with the E6 and E7 oncoproteins, particularly targeting the expression of interferon genes. Approximately 10% of individuals develop a persistent infection, and it is this cohort who is at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma.


Keywords*


human papilloma virus, early viral oncogenes, tumor suppressor genes, malignant transformation

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