Identification of tumor suppressor miRNAs by integrative miRNA and mRNA sequencing of matched tumor–normal samples in lung adenocarcinoma

Abstract

The roles of miRNAs in lung cancer have not yet been explored systematically at the genome scale despite their important regulatory functions. Here, we report an integrative analysis of miRNA and mRNA sequencing data for matched tumor–normal samples from 109 Korean female patients with non‐small‐cell lung adenocarcinoma (LUAD). We produced miRNA sequencing (miRNA‐Seq) and RNA‐Seq data for 48 patients and RNA‐Seq data for 61 additional patients. Subsequent differential expression analysis with stringent criteria yielded 44 miRNAs and 2322 genes. Integrative gene set analysis of the differentially expressed miRNAs and genes using miRNA–target information revealed several regulatory processes related to the cell cycle that were targeted by tumor suppressor miRNAs (TSmiR). We performed colony formation assays in A549 and NCI‐H460 cell lines to test the tumor‐suppressive activity of downregulated miRNAs in cancer and identified 7 novel TSmiRs (miR‐144‐5p, miR‐218‐1‐3p, miR‐223‐3p, miR‐27a‐5p, miR‐30a‐3p, miR‐30c‐2‐3p, miR‐338‐5p). Two miRNAs, miR‐30a‐3p and miR‐30c‐2‐3p, showed differential survival characteristics in the Tumor Cancer Genome Atlas (TCGA) LUAD patient cohort indicating their prognostic value. Finally, we identified a network cluster of miRNAs and target genes that could be responsible for cell cycle regulation. Our study not only provides a dataset of miRNA as well as mRNA sequencing from the matched tumor–normal samples, but also reports several novel TSmiRs that could potentially be developed into prognostic biomarkers or therapeutic RNA drugs.

MicroRNA‐338‐5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id‐1

“…Although miR‐338‐5p had been reported to be downregulated in non‐small‐cell lung carcinoma and glioblastoma, we have found that its expression was reduced in the majority of ESCC. Analysis of GEO datasets showed the same phenomenon in gastric, colon, and rectal cancers, thus suggesting that miR‐338‐5p has tumor suppressor functions in the gastrointestinal tract.…”

Altered expression of microRNA-30a-3p in papillary thyroid cancer and its association with clinicopathological characteristics

“…Next-generation sequencing and expression analysis of miRNAs in PTC and contralateral normal thyroid tissue specimens revealed miR-30a-3p to be among the most abundantly downregulated miRNAs in PTC [32]. Significantly decreased level of miR-30a-3p in tumor tissue compared to corresponding non-tumor tissue was also found in lung carcinoma [7,8,10,26], esophageal carcinoma [27], gastric cancer [28], colorectal cancer [14] and liver cancer [18].…”

“…One of the microRNAs with potential tumor suppressor activity that is frequently found to be deregulated and associated with aggressive tumor features and progression in various human cancers is miR-30a-3p. So far, downregulated expression of this member of the miR-30 family has been reported in lung cancer [7][8][9][10], breast cancer [11][12][13], colorectal cancer [14], bladder cancer [15], ovarian cancer [16], endometrial cancer [17], hepatocellular carcinoma [18], hematologic malignancies [19] and others.…”

The transcription factor Foxd3 induces spinal cord ischemia-reperfusion injury by potentiating microRNA-214-dependent inhibition of Kcnk2

“…MiRNAs play an important role in cell functions in most biological processes. Typical miRNAs negatively regulate the expression of multiple target genes 6 . Abnormalities in miRNAs may result in abnormal conditions such as microglial hyperactivation, persistent neuroinflammation and abnormal polarization of brain macrophages, which may contribute to the pathogenesis of neurological diseases such as glioma, ischemia and SCI 7 .…”