J Cancer 2021; 12(23):7120-7129. doi:10.7150/jca.60419 This issue

Research Paper

MiR-182-5p promotes the Metastasis and Epithelial-mesenchymal Transition in Non-small Cell Lung Cancer by Targeting EPAS1

Wenxiao Yang1#, Yinan Yin1#, Ling Bi1, Yichao Wang1, Jialin Yao1, Ling Xu1,2✉, Lijing Jiao1,3✉

1. Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2. Cancer Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
3. Institute of Clinical Immunology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
#These authors contributed equally to this work.

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Citation:
Yang W, Yin Y, Bi L, Wang Y, Yao J, Xu L, Jiao L. MiR-182-5p promotes the Metastasis and Epithelial-mesenchymal Transition in Non-small Cell Lung Cancer by Targeting EPAS1. J Cancer 2021; 12(23):7120-7129. doi:10.7150/jca.60419. Available from https://www.jcancer.org/v12p7120.htm

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Abstract

Graphic abstract

Background: Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of non-small cell lung cancer (NSCLC). However, the mechanisms through which miR-182-5p regulate NSCLC progression have not been established. This study aimed at evaluating the expression levels of miR-182-5p in human NSCLC and its function in lung cancer cells. Endothelial PAS Domain-containing protein 1 (EPAS1; also referred to as hypoxia-inducing factor 2A, HIF-2α) is a transcription factor that is responsible for induction of genes related to cell survival under hypoxia conditions. Hypoxia, an inherent feature of solid tumors, is associated with aggressive phenotypes, as well as resistance to radiotherapy and chemotherapy, which predict metastasis and poor prognosis.

Methods: The Cancer Genome Atlas (TCGA) dataset was used to investigate the association between miR-182-5p expression and clinicopathological characteristics as well as prognosis of NSCLC patients. Target genes of miR-182-5p were identified using the PITA, miRmap, microT, miRanda, PicTar, and TargetScan prediction tools. Transwell assays were performed to determine the potential functions of miR-182-5p in lung cancer cells. Luciferase reporter assays were performed to analyze regulation of the putative target of miR-182-5p while western blot assays were used to validate the luciferase results.

Results: miR-182-5p was found to be upregulated in NSCLC tissues and acted as an independent prognostic factor for tumor recurrence in NSCLC patients. Functionally, overexpression of miR-182-5p promoted lung cancer cell migration and invasion. Genome-wide gene expression analysis and luciferase report assays revealed that EPAS1 is a direct target of miR-182-5p. EPAS1 was negatively correlated with miR-182-5p expression in NSCLC tissues. Univariate and multivariate survival analyses identified EPAS1 as an independent prognostic factor for overall survival (OS) in NSCLC.

Conclusions: These findings imply that miR-182-5p promotes NSCLC progression by targeting EPAS1 and is, therefore, a potential indicator of tumor recurrence in NSCLC patients.

Keywords: EPAS1, miR-182-5p, NSCLC, Metastasis, EMT