Integrated analysis of miRNAs and DNA methylation identifies miR‐132‐3p as a tumor suppressor in lung adenocarcinoma

BACKGROUND: Aberrant miRNA expression and DNA methylation are two major epigenetic events in lung adenocarcinoma (LUAD). We conducted a combined analysis of the molecular changes in LUAD. METHODS: We analyzed differentially expressed miRNAs and methylated CpG loci in 489 LUAD tissues versus 49 normal lung tissues of the Cancer Genome Atlas (TCGA). The results were validated in cell lines and xenograft mouse models and additional pairs of 36 LUAD and 36 normal lung tissues. RESULTS: A total of 125 differentially expressed miRNAs and 145 differentially methylated CpG loci were identified in the LUAD versus normal lung tissues of TCGA data. Expression of the 22 miRNAs was inversely correlated with the 47 differentially methylated sites located in the miRNAs. Molecular and cellular function analysis showed that the abnormally methylated miRNAs were mainly involved in cell‐to‐cell signaling and interaction in airway cells. The DNA methylation status and altered expressions of miRNAs and their target genes were confirmed in 36 pairs of lung tumor and noncancerous lung tissues. Furthermore, aberrant miRNA expressions or DNA methylations alone could be involved in tumorigenesis of LUAD via different pathways. In addition, elevated miR‐132‐3p expression, reduced expression of its targeted gene (ZEB2), and decreased cell proliferation was observed in lung cancer cells treated with DNA methyltransferase inhibitor. Moreover, in vitro and in vivo analyses showed that miR‐132‐3p‐3p downregulation via DNA methylation promoted tumorigenicity of lung cancer by directly regulating ZEB2. CONCLUSIONS: The interaction between two epigenetic aberrations could have important functions in LUAD. miR‐132‐3p might act as a tumor suppressor in the tumorigenicity of LUAD. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Systemically investigating relationship between aberrant miRNA expression and DNA methylation in lung cancer could improve understanding of lung tumorigenesis and develop diagnostic and therapeutic targets. WHAT THIS STUDY ADDS: Three forms of relationships between the two epigenetic changes are defined. miR‐132‐3p is further identified as a tumor suppressor in lung cancer.