MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1

Abstract

MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR-138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1.

Overexpression of microRNA‐138 alleviates human coronary artery endothelial cell injury and inflammatory response by inhibiting the PI3K/Akt/eNOS pathway

“…Recent studies have reported that miRNAs regulate endothelial cell apoptosis and senescence-related pro-inflammatory status [7,8]. MiR-138 is an important member of miRNA family and has been shown to be a tumour suppressor in many studies [9,10]. Interestingly, miR-138 was reported to contribute to endothelial cell dysfunction when induced by pro-inflammatory cytokines [3].…”

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

“…Moreover, miR-138 was found to be a strong suppressor of YAP1 mRNA in oral squamous cell carcinoma (64) and in non-small cell lung cancer (65). The reported associations between decreased levels of either miR-509-3p or miR-138 in the studied types of cancer and poorer patient outcome (63)(64)(65), consolidating the influence of YAP1 in tumor progression. In fact, the contribution of YAP1 protein in tumor progression is so important that it was acknowledged as a pivotal molecular target in modern cancer treatment (5,34,38,51,52,66,67).…”

“…Pan et al found that miR-509-3p targeted YAP1 mRNA in a large group (293 cases from TCGA cohort) of ovarian cancer (63). Moreover, miR-138 was found to be a strong suppressor of YAP1 mRNA in oral squamous cell carcinoma (64) and in non-small cell lung cancer (65). The reported associations between decreased levels of either miR-509-3p or miR-138 in the studied types of cancer and poorer patient outcome (63)(64)(65), consolidating the influence of YAP1 in tumor progression.…”

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

“…MiR-138, miR-497 and miR-375 downregulated YAP1 to prevent tumor growth. 33,35,73 Pancreatic cancer YAP1 acted as an oncogene independently of KRAS. When KRAS was suppressed, YAP1 substituted for KRAS and rescued cancer cells from cell death in KRAS dependent cancer cells.…”

“…33,35 MiR-138 and miR-497 suppress YAP1 directly to decrease cancer cell proliferation, invasion, migration and tumor growth respectively. 33,35 In neuroendocrine lung cancers, activated miR-375 inhibits YAP1 directly to prevent tumor growth. 73 Although several known oncogenes are activated by oncogenic mutation in the coding region, YAP1 mutation is rare in NSCLC.…”