ASCL1 suppress ZFP36L1 expression by regulating miR124-3p expression in lung adenocarcinoma

Abstract

Background: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1). We previously demonstrated that ASCL1 exerts tumor-promoting effects by inducing a broad array of genes. MicroRNAs (miRNAs) regulate gene expression by binding to the 39UTRs of target mRNAs. Multiple miRNAs modulate a variety of cellular processes. However, miRNA profiles regulated by ASCL1 in lung adenocarcinoma cells remain unexplored. Method: We analyzed public database of gene expression profiling (RNA-sequencing and miRNA expression data). We also studied miRNA profiles in ASCL1-positive lung adenocarcinoma cells and identified a subset of miRNAs downregulated by ASCL1 knockdown. We examined functions of genes suppressed by miRNAs in ASCL1-positive lung adenocarcinoma cell line, VMRC-LCD. Result: Clinically relevant 15 genes including ZFP36L1 were identified that were suppressed by ASCL1 in lung adenocarcinoma. MiRNA array analysis were carried out to determine miRNAs regulated by ASCL1 in VMRC-LCD cells. We noted miR-124-3p which has been recently implicated with lung cancer. Interestingly, the 3’UTR region of ZFP36L1 gene contained target sequences for miR-124-3p. We further validated the effect of miR-124-3p mimics on ZFP36L1 expression. Overexpression of ZFP36L1 in VMRC-LCD cell line is associated with cell proliferation and induction of apoptosis. Conclusion: ASCL1 suppress ZFP36L1 expression by regulating miR124-3p expression in lung adenocarcinoma. It elucidated a novel regulatory network of mRNAs and miRNAs mediated by ASCL1 and related to neuroendocrine features.