Even with optimal surgery, many early-stage non-small cell lung cancer (NSCLC) patients die of recurrence. Unfortunately, there are no precise predictors for postoperative recurrence in early-stage NSCLC, and the recurrence mechanism is still unclear. In this study, we found that simultaneous overexpression of all miRNAs in the miR-23a/27a/24-2 cluster was closely associated with postoperative recurrence, β-catenin upregulation and promoter methylation of p16 and CDH13 in early-stage NSCLC patients. In addition, in vitro and in vivo experiments show that overexpression or inhibition of all miRNAs in the miR-23a/27a/24-2 cluster significantly stimulated or inhibited NSCLC cell stemness, tumorigenicity and metastasis. Furthermore, we demonstrated that the miR-23a/27a/24-2 cluster miRNAs activated Wnt/β-catenin signaling by targeting their suppressors and stimulated promoter methylation-induced silencing of p16 and CDH13 by affecting DNA methylation-related genes expression. Our findings suggest that simultaneous high expression of all miRNAs in the miR-23a/27a/24-2 cluster represents a new biomarker for predicting postoperative recurrence in early-stage NSCLC. The miR-23a/27a/24-2 cluster miRNAs stimulate early-stage NSCLC progression through simultaneously stimulating Wnt/β-catenin signaling, and promoter methylation-induced tumor suppressor genes silencing. In addition, simultaneous inhibition of all miRNAs in the miR-23a/27a/24-2 cluster may be a useful strategy for treatment of early-stage NSCLC recurrence.
Keywords: Wnt/β-catenin signaling; early-stage NSCLC; miR-23a/27a/24-2 cluster; postoperative recurrence; tumor suppressor gene silencing.
© 2021 The Authors.