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Abstract
HPV encoded proteins can elicit ectopic protein–protein interactions that re-wire signaling pathways, in a mode that promotes malignancy. Moreover, accumulating data related to HPV is now providing compelling substantiation of a central role played by HPV in escaping immunosurveillance and impairment of apoptotic response. What emerges is an intricate network of Wnt, TGF, Notch signaling cascades that forms higher-order ligand–receptor complexes routing downstream signaling in HPV infected cells. These HPV infected cells are regulated both extracellularly by ligand receptor axis and intracellularly by HPV encoded proteins and impair TRAIL mediated apoptosis. We divide this review into different sections addressing how linear signaling pathways integrate to facilitate carcinogenesis and compounds that directly or indirectly reverse these aberrant interactions offer new possibilities for therapy in cancer. Although HPV encoded proteins mediated misrepresentation of pathways is difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can target dysregulated pathways in HPV infected cervical cancer cells, thus setting the stage for preclinical models and clinical trials.
Highlights
There is an overwhelming list of research work that underlines the fact that HPV encoded proteins control cell cycle progression, apoptosis and cell differentiation, and have emerged as fundamental regulators of cervical cancer
Recent studies have revealed an extraordinarily complex network of proteins that is regulated by HPV encoded proteins
It has lately been shown that Hh signaling is not induced directly by HPV-encoded proteins instead Hh-activating mutations are selected in cells initially immortalized by HPV [183]
Summary
There is an overwhelming list of research work that underlines the fact that HPV encoded proteins control cell cycle progression, apoptosis and cell differentiation, and have emerged as fundamental regulators of cervical cancer. It has been shown that HPV encoded E5 protein utilizes cAMP/PKA/CREB pathway to stimulate the expression of genes [31] It needs to be tested with reference to pro-apoptotic and antiapoptotic gene subsets in cervical cancer cells. P53 mediated regulation of miRNA subsets in HPV infected cervical cancer It is clear that HPV encoded proteins target p53 to inhibit apoptosis of host cells. MiR-375 is a tumor suppressor gene and is downregulated in cervical cancer cells it has been reported that HPV16 E6/E7 does not directly regulate miR-375 expression [80,81,82,83,148]. Binding sites for E2F1 and E2F3 have been identified in the promoter of miR-15b and targeted inhibition of HPV16-E7 resulted in downregulation of miR-15b in cancer cells [159] Figure 4. We have discussed common strategies used by HPV encoded proteins for modulation of protein network to impair apoptosis in host cells
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