MiR-4739 promotes epithelial-mesenchymal transition and angiogenesis in "driver gene-negative" non-small cell lung cancer via activating the Wnt/β-catenin signaling.

Abstract

"Driver gene-negative" non-small cell lung cancer (NSCLC) currently has no approved targeted drug, due to the lack of common actionable driver molecules. Even though miRNAs play crucial roles in various malignancies, their roles in "driver gene-negative" NSCLC keep unclear. miRNA expression microarrays were utilized to screen miRNAs associated with "driver gene-negative" NSCLC malignant progression. Quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH) were employed to validate the expression of miR-4739, and its correlation with clinicopathological characteristics was analyzed in tumor specimens using univariate and multivariate analyses. The biological functions and underlying mechanisms of miR-4739 were investigated both in vitro and in vivo. our research demonstrated, for the first time, that miR-4739 was substantially increased in "driver gene-negative" NSCLC tumor tissues and cell lines, and overexpression of miR-4739 was related to clinical staging, metastasis, and unfavorable outcomes. Functional experiments discovered that miR-4739 dramatically enhanced tumor cell proliferation, migration, and metastasis by promoting the epithelial-to-mesenchymal transition (EMT). Meanwhile, miR-4739 can be transported from cancer cells to the site of vascular epithelial cells through exosomes, consequently facilitating the proliferation and migration of vascular epithelial cells and inducing angiogenesis. Mechanistically, miR-4739 can activate Wnt/β-catenin signaling both in tumor cells and vascular epithelial cells by targeting Wnt/β-catenin signaling antagonists APC2 and DKK3, respectively. Our work identifies a valuable oncogene, miR-4739, that accelerates malignant progression in "driver gene-negative" NSCLC and serves as a potential therapeutic target for this group of tumors.