miR-186 regulates chemo-sensitivity to paclitaxel via targeting MAPT in non-small cell lung cancer (NSCLC)

Abstract

miR-186 has been reported to be implicated in tumorigenesis and chemoresistance in a few cancer types. However, its role in regulating chemoresistance has not been investigated in non-small cell lung cancer (NSCLC). To examine the effects of miR-186 on chemosensitivity in NSCLC, an miR-186 mimic and inhibitor were transfected, followed by CellTiter-Glo® assay in NSCLC cell lines. Western blot and luciferase assay were performed to investigate the direct targeting of miR-186. A xenograft mouse model was used to examine the in vivo chemosensitizing function of miR-186. We found that overexpression of miR-186 sensitized A549 and H1299 cells to paclitaxel, whereas inhibition of miR-186 conferred resistance in these cells. MAPT was the direct target of miR-186 which was required for the regulatory role of miR-186 in chemoresistance. This chemosensitizing function was partially due to the induction of the p53 mediated apoptotic pathway. The miR-186 mimic enhanced the tumor growth inhibitory effects of paclitaxel in A549 xenografts. In addition, miR-186 was found to be down-regulated in NSCLC patients who were chemoresistant and this down-regulation was associated with poor survival. Taken together, our study demonstrated that miR-186 regulates the chemoresistance of NSCLC cells by modulating the MAPT expression level both in vitro and in vivo. miR-186 may represent a new therapeutic target for the improvement of the clinical outcome in NSCLC.

miR‑186 functions as a tumor suppressor in osteosarcoma cells by suppressing the malignant phenotype and aerobic glycolysis

“…The group transfected with miR-186 and control constructs exhibited the minimum number of cells passing through the chamber, which could be abolished upon transfection with PTTG1 constructs. * P<0.05. perform a pivotal role in muscle differentiation (14), miR-186 has also been found to participate in many biological and pathological processes, including cell proliferation, apoptosis and invasion (7,15). Recently, the tumor suppressive role of miR-186 has been widely reported in many cancers, such as in prostate cancer (PC), where miR-186 inhibited the expression of VeGF and reduced tumor growth by influencing the PGe-2-induced VeGF-signaling pathway (16).…”

“…In addition, our previous study reported that miR-140 was downregulated in OS tissues and functioned as a tumor suppressor in OS, as overexpression of miR-140 significantly inhibited cell proliferation in vitro and tumor growth in vivo by targeting the HDAC4 signaling pathway (6). Furthermore, miR-186 has been reported to function as a tumor suppressor in a variety of malignancies and regulate the chemosensitivity of non-small cell lung cancer cells to paclitaxel by targeting the MAPT-signaling pathway (7). In idiopathic pulmonary fibrosis cells, it has been closely related with the overexpression of collagen V and epithelial-to-mesenchymal transition (EMT) (8).…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Importantly, induced overexpression of miR-137 underlined a tumour suppressive role of this miRNA in chemosensitivity by the inhibition of cell growth and angiogenesis in vivo. In a xenograft mouse model, miR-186 also showed tumour growth inhibitory functions [128]. This miRNA directly targeted MAPT and the chemosensitizing function of miR-186 was partially caused by the induction of the p53-mediated apoptotic pathway.…”

A review of microRNAs related to the occurrence, diagnosis, and prognosis of non-small cell lung cancer

“…Chen et al [62] reported that decreased miR-27b expression was associated with docetaxel resistance of NSCLC, while up-regulation of miR-27b could inhibit NSCLC cell viability and enhance the docetaxel sensitivity of NSCLC cells through direct inhibition of EGFR expression. Ye et al [63] showed that overexpression of miR-186 sensitized NSCLC cells to paclitaxel, whereas inhibition of miR-186 conferred resistance in NSCLC cells. In validation, miR-186 was found to be down-regulated in NSCLC patients who were paclitaxel-resistant, and this decrease was associated with poor survival.…”