Downregulation of DNMT3A by miR-708-5p inhibits lung cancer stem cell-like phenotypes through repressing Wnt/{beta}-catenin signaling

Purpose: Lung cancer is the leading cause of cancer death in the world, and emerging evidences suggest that lung cancer stem cells (CSCs) are associated with its poor prognosis, tumor recurrence and therapy resistance. Here we reveal a novel role for miR-708-5p in inhibiting lung cancer stem cell-like features. Experimental Design: Phenotypic effects of miR-708-5p on the lung CSC-like properties were examined by in vitro sphere formation assay and in xenografted animal models. Immunoblotting, dual luciferase reporter, and immunocytochemistry were performed to determine the target of miR-708-5p. DNA methylation of CDH1 promoter region was tested using bisulfate sequencing. Genome-wide miRNA sequencing data of 990 patients from the cancer genome atlas (TCGA) dataset and 148 patients from China cohort were analyzed to excavate the pathogenic implications of miR-708-5p. Results: Expression of miR-708-5p inhibits the CSC traits of NSCLC cells in vitro while antagonizing miR-708-5p promotes tumorigenesis in vivo. MiR-708-5p directly suppresses the translation of DNMT3A, which results in a substantial reduction of global DNA methylation and the up-regulated expression of tumor suppressor CDH1. The up-regulation of CDH1 decreased the activity of Wnt/β-catenin signaling and then impaired the stemness charactertics of NSCLC cells. Clinically, patients with high miR-708-5p expression show significantly better survival and lower recurrence. Furthermore, miR-708-5p has a promising potential to apply to differentiating histological subtypes in NSCLC. Conclusion: Our findings support that miR-708-5p suppresses NSCLC initiation, development and stemness through interfering DNMT3A-dependent DNA methylation. MiR-708-5p may function as a novel diagnostic and prognostic biomarker in NSCLC.

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