Long non-coding RNAs (lncRNAs) have shown critical roles in multiple cancers via competitively binding common microRNAs. miR-214 has been proved to play tumour suppressive roles in various cancers, including cervical cancer. In this study, we identified that lncRNA LINC01535 physically binds miR-214, relieves the repressive roles of miR-214 on its target EZH2, and therefore up-regulates EZH2 protein expression. Intriguingly, we also found that EZH2 directly represses the expression of miR-214. Thus, miR-214 and EZH2 form double negative regulatory loop. Through up-regulating EZH2, LINC01535 further represses miR-214 expression. Functional experiments showed that enhanced expression of LINC01535 promotes cervical cancer cell growth, migration and invasion in vitro and cervical cancer xenograft growth in vivo. Reciprocally, LINC01535 knockdown suppresses cervical cancer cell growth, migration and invasion. Activation of the miR-214/EZH2 regulatory loop by overexpression of miR-214 or silencing of EZH2 reverses the roles of LINC01535 in promoting cervical canc`er cell growth, migration and invasion in vitro and cervical cancer xenograft growth in vivo. Clinically, LINC01535 is significantly up-regulated in cervical cancer tissues and correlated with advanced clinical stage and poor prognosis. Moreover, the expression of LINC01535 is reversely associated with the expression of miR-214 and positively associated with the expression of EZH2 in cervical cancer tissues. In conclusion, this study reveals that LINC01535 promotes cervical cancer progression via repressing the miR-214/EZH2 regulatory loop.
Keywords: cervical cancer; feedback loop; long non-coding RNA; microRNA; progression.
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.