The role of miR-409-3p in regulation of HPV16/18-E6 mRNA in human cervical high-grade squamous intraepithelial lesions.

Cervical cancer is one of the most common malignancies in women. MicroRNAs (miRNAs) are involved in a variety of fundamental cellular processes, including carcinogenesis. The potential utilization of aberrantly expressed miRNAs as novel biomarkers in cervical cancer diagnostics is growing. We investigated miRNA expression profiles during the progression of dysplasia in cervical epithelium to identify aberrantly expressed miRNAs. High-throughput miRNA profiling of high-grade precancerous lesions identified 79 miRNAs showing significant difference in expression values compared to normal cervical epithelium. Ten selected miRNAs were subsequently measured in an independent group of samples to validate them as promising biomarkers of cervical carcinogenesis. MicroRNAs miR-10b-5p, miR-34c-5p, miR-409-3p and miR-411-5p were confirmed as downregulated, while miR-10a-5p, miR-132-3p, miR-141-5p were significantly upregulated in dysplastic cervical tissues. Further investigation revealed an inverse correlation of miR-409-3p with E6 mRNA levels in precancerous cervical lesions. Subsequent in vitro analyses showed a direct involvement of this miRNA in the regulation of E6 oncogene levels, thus confirming a potential tumor suppressor function of miR-409-3p in cervical malignancies. Hence, miR-409-3p may represent a useful early marker and a potential therapeutic target for cervical cancer.

Sommerova L ，Anton M ，Bouchalova P ，Jasickova H ，Rak V ，Jandakova E ，Selingerova I ，Bartosik M ，Vojtesek B ，Hrstka R ... -  《-》

Human Papillomavirus 16 Oncoproteins Downregulate the Expression of miR-148a-3p, miR-190a-5p, and miR-199b-5p in Cervical Cancer.

Han MS ，Lee JM ，Kim SN ，Kim JH ，Kim HS ... -  《-》

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells.

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 TMPOP2 promoter to repress the transcription of the TMPOP2 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 E6/E7 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 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 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 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 of the oncogenic activities of human papillomaviruses and lncRNAs.

He H ，Liu X ，Liu Y ，Zhang M ，Lai Y ，Hao Y ，Wang Q ，Shi D ，Wang N ，Luo XG ，Ma W ，Zhang TC ... -  《-》

miR-3156-3p is downregulated in HPV-positive cervical cancer and performs as a tumor-suppressive miRNA.

Xia YF ，Pei GH ，Wang N ，Che YC ，Yu FS ，Yin FF ，Liu HX ，Luo B ，Wang YK ... -  《Virology Journal》

Dependence of intracellular and exosomal microRNAs on viral E6/E7 oncogene expression in HPV-positive tumor cells.

Honegger A ，Schilling D ，Bastian S ，Sponagel J ，Kuryshev V ，Sültmann H ，Scheffner M ，Hoppe-Seyler K ，Hoppe-Seyler F ... -  《-》