MiR-154-3p and miR-487-3p synergistically modulate RHOA signaling in the carcinogenesis of thyroid cancer.

Abstract

Background: miRs family members are often thought to have extensively overlapping targets and synergistically to modulate target gene expression via post-transcriptional repression. The present study was to determine whether miR-154-3p and miR-487-3p synergistically collaborated to regulate RHOA signaling in the carcinogenesis of thyroid cancer. Materials and methods: Candidate miRs were filtrated using miR microarray assays. Gene and protein expression levels were analyzed using RT-qPCR and Western blotting, respectively. Cell growth was evaluated using CCK8 assays and nude-mouse transplanted tumor experiments. Cell apoptosis was detected using Annexin V-FITC double staining. Results: miR-154-3p and miR-487-3p were significantly decreased in 63 thyroid cancer tissues and cell lines compared with those in paired non-tumor tissues and normal thyroid follicular epithelial cells. Low expression levels of miR-154-3p and miR-487-3p significantly correlated with tumor size, TNM stage, histological grade, lymph node metastasis and shorter overall survival in patients with thyroid cancer. Furthermore, the protein expression of RHOA was significantly inversely correlated with miR-154-3p (r = −0.404; P = 0.001) and miR-487-3p (r = −0.456; P < 0.001) expression in thyroid cancer tissues. We experimentally validated that miR-154-3p and miR-487-3p synergistically blocked thyroid cancer cell growth in vitro and in vivo. However, the anti-proliferative and pro-apoptotic activities of miR-154-3p/487-3p were neutralized by RHOA overexpressed vectors. Conclusions: Our present findings expounded a novel signal cascade employing miR-154-3p/487-3p and RHOA to fine-tune thyroid cancer cell proliferation and apoptosis. We corroborated that suppression of RHOA by miR-154-3p/487-3p may be a valuable therapeutic target for impeding thyroid cancer progression.