Long noncoding RNA TOB1-AS1 an epigenetically silenced gene functioned as a novel tumor suppressor by sponging miR-27b in cervical cancer

摘要

Cervical cancer is one of the most common cancers in females, accounting for a majority of cancer-related deaths in worldwide. Long non-coding RNAs (lncRNAs) have been identified as critical regulators in many tumor-related biological processes. Thus, investigation into the function and mechanism of lncRNAs in the development of cervical cancer is very necessary. In this study, we found that the expression of TOB1-AS1 was significantly decreased in cervical cancer tissues compared with the adjacent normal tissues. The methylation status of TOB1-AS1-related CpG island was analyzed using methylation specific PCR and bisulfite sequencing analysis, revealing that the aberrant hypermethylation of TOB1-AS1-related CpG island was frequently observed in primary tumors and cervical cancer cells. The expression of TOB1-AS1 in cervical cancer cells could be reversed by demethylation agent treatment. Functionally, overexpression of TOB1-AS1 significantly inhibited cell proliferation, cell cycle progression, invasion and induced apoptosis, while knockdown of TOB1-AS1 exhibited the opposite effect. Furthermore, it was determined that TOB1-AS1 was able to bind and degrade the expression of miR-27b. Upregulation of miR-27b promoted cell growth, cell cycle transition from G1 phase to S phase, and invasion and reduced apoptosis, phenomenon could be reversed by TOB1-AS1. Inhibition of miR-27b attenuated the promotive effect of si-TOB1-AS1 on cellular processes. Upregulation of TOB1-AS1 also suppressed tumor growth in vivo. Clinically, methylation of TOB1-AS1 and low expression of TOB1-AS1 was significantly correlated with tumor stage and tumor size, respectively. Univariate and multivariate analyses confirmed that low level of TOB1-AS1 was an independent risk factor for death. In conclusion, we suggested that the epigenetically silenced TOB1-AS1 was unable to restrain miR-27b, which contributed to cervical cancer progression.