Downregulation of miR-146a promotes tumorigenesis of cervical cancer stem cells via VEGF/CDC42/PAK1 signaling pathway

Abstract

Cervical cancer (CC) is a primary gynecological malignancy worldwide. Cancer stem cells (CSCs) possess enhanced tumor-initiating and self-renewing abilities. MicroRNAs (miRNAs) play essential roles in CSCs’ tumorigenesis. This study investigated the effects of miR-146a on CSCs’ tumorigenesis and invasion. Tumorsphere cells (TCs) were enriched from the HeLa cell line. Real-time PCR, Western blots, ALDH assays, colony formation and invasion assays, luciferase reporter assays and the Xenograft mouse model were used to determine the underlying mechanism of CC. The results showed that TCs displayed higher ALDH activity and miR-146a was upregulated in differentiated TCs. Moreover, miR-146a inhibitor increased colony formation and cell invasion in TCs while miR-146a mimics displayed the opposite roles. An inverse relationship between miR-146a and VEGF expression was found in TCs and the luciferase reporter assay revealed that VEGF was a direct target of miR-146a. Inhibition of VEGF reversed the effects of miR-146a inhibitor on TCs. The activated CDC42/PAK1 signaling was associated with TCs’ tumorigenesis and invasion. Furthermore, miR-146a inhibitor-treated TCs promoted tumor growth in nude mice. Altogether, the results suggest that miR-146a modulated TCs’ tumor formation and invasion and was associated with VEGF/CDC42/PAK1 signaling. This study provided insight into developing new therapeutic strategies for CC.