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Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer

Oncogene volume 33, pages 1181–1189 (2014)Cite this article

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Abstract

We have previously shown that miR-486-5p is one of the most downregulated micro RNAs in lung cancer. The objective of the study was to investigate the role of miR-486-5p in the progression and metastasis of non-small-cell lung cancer (NSCLC). We evaluated miR-486-5p expression status on 76 frozen and 33 formalin-fixed paraffin-embedded tissues of NSCLC by quantitative reverse transcriptase PCR to determine its clinicopathologic significance. We then performed function analysis of miR-486-5p to determine its potential roles on cancer cell migration and invasion in vitro and metastasis in vivo. We also investigated the target genes of miR-486-5p in lung tumorigenesis. miR-486-5p expression level was significantly lower in lung tumors compared with their corresponding normal tissues (P<0.0001), and associated with stage (P=0.0001) and lymph node metastasis of NSCLC (P=0.0019). Forced expression of miR-486-5p inhibited NSCLC cell migration and invasion in vitro and metastasis in mice by inhibiting cell proliferation. Furthermore, ectopic expression of miR-486-5p in cancer cells reduced ARHGAP5 expression level, whereas miR-486-5p silencing increased its expression. Luciferase assay demonstrated that miR-486-5p could directly bind to the 3′-untranslated region of ARHGAP5. The expression level of miR-486-5p was inversely correlated with that of ARHGAP5 in lung tumor tissues (P=0.0156). Reduced expression of ARHGAP5 considerably inhibited lung cancer cell migration and invasion, resembling that of miR-486-5p overexpression. miR-486-5p may act as a tumor-suppressor contributing to the progression and metastasis of NSCLC by targeting ARHGAP5. miR-486-5p would provide potential diagnostic and therapeutic targets for the disease.

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Acknowledgements

This work was supported by Grants 81101482 from the National Natural Science Foundation of China and Grants C2011206001 from the Natural Science Foundation of Hebei province, China (to LX) and American Cancer Society-Research Scholar Grant in Basic, Preclinical, Clinical and Epidemiology Research-115154AF109040, National Cancer Institute (NCI)-R01CA161837-01, an exploratory research grant from the Maryland Stem Cell Research Fund, and VA-Merit grant-I01 CX000512-01 (to FJ).

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  1. J Wang and X Tian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, Shijiazhuang, China

    J Wang, X Tian, R Han, H Shen, L Xue, X Yan & L Xing

  2. Department of Pathology, Second Hospital of Hebei Medical University, Shijiazhuang, China

    X Zhang

  3. Department of Pathology, Tumor Hospital of Hebei Medical University, Shijiazhuang, China

    X Wang & Y Liu

  4. Department of Pathology, University of Maryland School of Medicine, Baltimore, USA, MD

    J Shen, K Mannoor, S A Stass & F Jiang

  5. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    J Deepak

  6. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    J M Donahue

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  1. J Wang
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Correspondence to L Xing or F Jiang.

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Wang, J., Tian, X., Han, R. et al. Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene 33, 1181–1189 (2014). https://doi.org/10.1038/onc.2013.42

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