Human papillomavirus E6/E7 and lncRNA TMPOP2 mutually upregulated gene expression in cervical cancer cells.

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Human papillomavirus E6/E7 and lncRNA TMPOP2 mutually upregulated gene expression in cervical cancer cells.

J Virol. 2019 Feb 06;:

Authors: He H, Liu X, Liu Y, Zhang M, Lai Y, Hao Y, Wang Q, Shi D, Wang N, Luo XG, Ma W, Zhang TC

Abstract
TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remains largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus HPV16/18 E6 and E7 in cervical cancer cell CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53-response elements in the TMPOP2 promoter to repress the transcription of TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor miRNAs miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the lncRNA TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities.IMPORTANCE: Type 16 and type 18 HPVs are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of lncRNAs in cervical cancer although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings to the oncogenic activities of human papillomaviruses and lncRNAs.

PMID: 30728257 [PubMed - as supplied by publisher]

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