Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, Tianjin University of Science and Technology, Tianjin, China
College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
J Virol. 2019 Apr 3;93(8). doi: 10.1128/JVI.01808-18. Print 2019 Apr 15.
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 the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines 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 promoter to repress the transcription of the gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (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 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. Human papillomaviruses 16 and 18 (HPV16/18) 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 long noncoding RNAs (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 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 of the oncogenic activities of human papillomaviruses and lncRNAs.
TMPOP2 先前被认为是一种致癌的长链非编码 RNA，在宫颈癌细胞中过度表达，通过招募转录抑制因子 EZH2 到基因启动子来抑制 E-钙黏蛋白基因的表达。迄今为止，TMPOP2 在宫颈癌中的功能和调节仍知之甚少。在此，我们发现 TMPOP2 的表达与宫颈癌细胞系 CaSki 和 HeLa 中的人乳头瘤病毒 16/18（HPV16/18）E6 和 E7 相关。HPV16/18 靶向降解的肿瘤抑制因子 p53 被证明与基因启动子中的两个 p53 反应元件结合，从而抑制基因的转录。相反，异位表达的 TMPOP2 被证明可以隔离肿瘤抑制 microRNAs（miRNAs）miR-375 和 miR-139，它们靶向 HPV16/18 E6/E7 mRNA，导致 HPV16/18 基因的上调。因此，HPV16/18 E6/E7 和长链非编码 RNA（lncRNA）TMPOP2 形成正反馈回路，相互解除对宫颈癌细胞中基因表达的抑制。此外，RNA 测序和细胞周期分析的结果表明，下调会损害细胞周期基因的表达，诱导细胞周期停滞，并抑制 HeLa 细胞的增殖。总之，我们的研究结果表明，TMPOP2 和 HPV16/18 E6/E7 在宫颈癌细胞中相互加强表达，以增强肿瘤发生活性。人乳头瘤病毒 16 和 18（HPV16/18）是宫颈癌的主要致病因素。病毒蛋白 HPV16/18 E6 和 E7 在癌细胞中持续表达，以维持致癌表型。越来越多的证据表明，HPV 与宫颈癌中长链非编码 RNA（lncRNA）的失调有关，尽管在大多数情况下，其机制尚不清楚。TMPOP2 是一种新发现的在宫颈癌中过度表达的 lncRNA。然而，宫颈癌细胞中上调的机制在很大程度上仍然未知，其与 HPV 的关系仍然难以捉摸。我们研究的意义在于揭示 HPV16/18 E6/E7 与 TMPOP2 的相互上调及其分子机制。本研究将扩大我们对人乳头瘤病毒和 lncRNA 的致癌活性的认识。
