Human Papillomavirus16 E6 Disturbs Cervical Cancer Cell Metabolism By Upregulating Malic Enzyme Expression

Background:The persistent infection of High-risk HPV16 is the driver of cervical cancer,and it is the most common and dangerous type of HPV,which not only exists in cervical precancerous lesions but also in cervical cancer.E6 and E7,as the major oncoproteins of HPV16,promoting the immortalization of host cells.Research has shown that HPV16 E6 allows cells to proliferate into tumors by interacting with some cellular factors.Cell cycle arrest both protects multicellular organisms from cancer and contributes to their ageing.Few connections between HPV E6 and cell cycle arrest have been established.The malic enzymes,as the rate-limiting enzyme,are very important for the tricarboxylic-acid-cycle,which regulate the cell metabolism.Here,we investigated the potential association between HPV E6 and Malic enzyme and explore the possible biological meaning.Methods: The methods and processes of immunohistochemical staining were performed were used to check the malic enzyme 2 expression in cervical cancer tissue and its adjacent normal tissue.Using the lentivirus-mediated sh RNA to knock down the expression of HPV E6 gene in cervical cancer Ca Ski cells,and the effect of HPV E6 on the expression and content of malic enzyme 2 in cervical cancer cell lines was detected by Western blot and fluorescence quantitative PCR.And determine its effect on the function of malic enzyme 2.Malic enzyme 2 expression of cervical cancer was down-regulated by si RNA,then flow cytometry was used to detect cell cycle.Malic enzyme in cervical cancer cells was knocked down by lentivirus-mediated si RNA,then the effect of malic enzyme on tumorigenesis was verified by colony formation analysis and nude mouse tumor xenograft.Results: The malic enzyme protein was overexpression in cervical cancer tissue.The HPV16 E6 up-regulated malic enzyme expression at both transcription and translation levels.Inhibition of the expression of malic enzyme2 in cervical cancer cells impeded its tumorigenesis through restore senescence especially in HPV positive ones.The colony formation analysis reveals that the high expression of malic enzyme 2 was related to cervical cancer,this result also showed in the tumor formation in the nude mice.Conclusion: Malic enzyme 2 overexpression is related to its carcinogenesis.Target therapy by destroy malic enzyme 2 combining with HPV E6 could be a promising treatment method of cervical cancer.