Page 34 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 2
Oncogenesis
Proliferation, immortalization and genomic instability
Cervical carcinogenesis is characterized by a combination of uncontrolled cell proliferation and immortalization and genomic instability, for which the early viral genes E6 and E7 are largely responsible. The combined action of HPV E6 and E7 leads to cell proliferation and immortalization, through processes summarized in figure 2. Furthermore, it induces genomic instability, which is the result of deregulation of the centrosome cycle and direct DNA damage. As a result, a proliferating cell population will evolve with chromosomal aberrations.
Figure 2. Cellular processes in cervical carcinogenesis following HPV infection.
E6 acts through inhibition of p53, a well-known inductor of apoptosis. Additionally, E6 leads to the increase of telomerase activity by activation of transcription of telomerase reverse transcriptase, leading to sustained telomerase, necessary for cell immortalization. E7 inactivates tumour suppressor protein retinoblastoma (Rb), thereby increasing free E2F, leading to cellular proliferation. Cells in which the normal actions of Rb are suppressed by E7 are characterized
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