Downregulation of DNMT3A by miR-708-5p Inhibits Lung Cancer Stem Cell–like Phenotypes through Repressing Wnt/beta-catenin Signaling

Research output: Contribution to journalArticle

Authors

  • Tianchi Liu
  • Xiaoping Wu
  • Tong Chen
  • Zewei Luo
  • Xiaohua Hu

Colleges, School and Institutes

External organisations

  • Population and Quantitative Genetics Laboratory, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University

Abstract

Purpose: Lung cancer is the leading cause of cancer-related death in the world, and emerging evidences suggest that lung cancer stem cells (CSC) are associated with its poor prognosis, tumor recurrence, and therapy resistance. Here we reveal a novel role for miR-708-5p in inhibiting lung CSC-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 upregulated expression of tumor suppressor CDH1. The upregulation of CDH1 decreased the activity of Wnt/β-catenin signaling and then impaired the stemness characteristics 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 histologic subtypes in NSCLC.


Conclusions: 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.

Details

Original languageEnglish
Pages (from-to)1748-1760
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number7
Early online date28 Sep 2017
Publication statusPublished - 1 Apr 2018