Molecular mechanisms of HPV mediated neoplastic progression

Abstract

Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets.

Keywords: Carcinogenesis; Cervical cancer; HPV integration; Neoplastic progression.

Fig. 1

Conceptual model of viral integration. 1. Induction of DSB by ROS/NOS/Viral protein 2. DNA damage induces DDR (DNA damage response), ATM/ATR and P53 get activated to repair the damage. 3. HPV oncogenes deactivate the normal function of DDR molecules and DNA damage failed to be recognized. E7 degrades claspins and attenuate DNA damage checkpoints, while E6 degrades p53 and base excision repair gets suppressed so that the genomic DNA remains unrepaired and cell cycle proceeds. 4. Virus utilizes the DDR machinery for its replication which increases the availability of episomal DNA for integration. Breaks in the circular viral DNA may occur due to replication stress. 5. Virus and host genome come to a close proximity mediated by the BRD4-E2 complex. 6. Fusion between host and viral genome is accomplished either by Nonhomologous mediated end joining or homologous recombination repair pathway

Fig. 2

HPV-driven carcinogenesis: a multistep molecular mechanism of host-viral interaction. The initial outcome of carcinogenesis is modulated by both viral (high-risk versus low-risk HPV types, HPV integration) and host factors (inflammatory response, oxidative stress). Inflammatory response upon initial infection such as IFN response plays role in reducing episomal HPV resulting clearance of infection. Integration of HPV is initiated with DNA damage. The IFN induced loss of episomal HPV and down-regulation of E2 leads to the selection of cells with integrated HPV genomes expressing higher levels of E6 and E7. Once the early genes E6 &E7 are expressed, TLR9 downregulated and IFN response impaired, resulting a conducive milieu for immune evasion and persistent infection. Upregulation of E6/E7 increases genetic instability and chromosomal rearrangements that increase the risk of integration. Overexpression of E6/E7 leads to deregulation of the cell cycle via p53 & Rb degradation, deregulation of oncogenes and miRNAs expression. Epigenetic and genetic modification in viral and host genome leads to the deregulation of E6 &E7 oncogenes, and host tumor suppressor genes that lead to carcinogenesis. Oxidative modification of TFs also leads to altered gene expression and carcinogenesis