Unique microRNAs in lung adenocarcinoma groups according to major TKI sensitive EGFR mutation status

Min Gyoung Pak, Chang-Hun Lee, Woo-Jeong Lee, Dong-Hoon Shin, Mee-Sook Roh

Lung cancer is the leading cause of cancer mortality, despite development of therapeutic strategies. Altered expression of microRNAs(miRNAs) in human malignancies have been well recognized as diagnostic and prognostic indicators, including lung cancer. This study aims to delineate the clinicopathologic significance of three unique miRNAs in adenocarcinoma according to major sensitive EGFR mutation status. One-hundred and three formalin-fixed paraffin-embedded (FFPE) tissues were collected from lung adenocarcinoma patients who underwent surgery and epidermal growth factor receptor (EGFR) mutation study. The samples were divided into three groups which include EGFR mutation in exons 19 and 21 and wild type. Some representative cases from each group were profiled using commercial miRNA microarray plates. Three significant miRNAs were selected and they were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), using collective cases of FFPE samples. We identified three microRNAs (miR-34c, miR-183, and miR-210) which showed significantly altered expression in all groups of lung adenocarcinoma by microarray study. Compared to normal control lung tissue, down-regulation of miR-34c and up-regulation of miR-183 and miR-210 were identified in caner groups (p < 0.05 for each). We validated the expression of three miRNAs by qRT-PCR. Expression levels of miR-34c, miR-183, and miR-210 were significantly different between normal control group and cancer groups (p = 0.034, <0.000, and 0.036, respectively). Moreover, expression level of miR-183 was significantly higher in EGFR mutation groups than wild type group (p = 0.028). Higher expression levels of three miRNAs were positively related to poor tumor differentiation. Increased expression of miR-183 was positively associated with lymphovascular invasion (p = 0.037). Aberrant expression of miR-210 was independently associated with T stage (p = 0.019), and TNM stage (p = 0.007). However, there was noted a limited statistical significance. In EGFR exon 19 mutation group, miR-34c high expression group showed poor overall survival than low expression one by univariate Kaplan-Meier method. (p = 0.035). Here, we show that miR-34c may act as a potential tumor suppressor gene and miR-183 and miR-210 have a potential oncogenic role in pulmonary adenocarcinoma. This study also suggests different miRNA expression between EGFR mutation group and wild type group. Consequently, further studies of the biology of miRNAs may lead to diagnostic and prognostic biomarkers in pulmonary adenocarcinoma.