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The molecular mechanism of microRNA-145 to suppress invasion–metastasis cascade in gastric cancer

Oncogene volume 32, pages 491–501 (2013)Cite this article

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Abstract

Invasion and metastasis are the major features of malignant tumors that are responsible for 90% of cancer-related deaths. Recently, microRNAs have been discovered to have a role in suppressing tumor metastasis. This study's aim was to clarify the roles of miR-145 in gastric carcinomas and its underlying molecular mechanism in regulating tumor metastasis. Here, we demonstrate a stepwise downregulation of miR-145 level in nontumorous gastric mucosa, primary gastric cancers and their secondary metastases. In vitro analysis of miR-145's ectopic expression and loss-of-function suggests that it suppresses gastric cancer cell migration and invasion. In vivo spontaneous metastasis and experimental metastasis assay further confirm its function in suppressing the invasion–metastasis cascade, including impairing local invasion and inhibiting hematogenous metastasis in gastric cancers. Furthermore, we identified a novel mechanism of miR-145 to suppress metastasis. N-cadherin (CDH2) was proved to be a direct target of miR-145, using luciferase assay and western blot. Re-expressing N-cadherin in miR-145-transfected cells reverses their migration and invasion defects. Although not a direct target of miR-145, matrix metallopeptidase 9 (MMP9), but not MMP2, was also significantly decreased in miR-145-expressing cells. We suggest that miR-145 suppresses tumor metastasis by inhibiting N-cadherin protein translation, and then indirectly downregulates its downstream effector MMP9.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 30972929, 81172351) and the Natural Science Foundation of Shandong Province of China (No. ZR2010HM075). We thank Chun-Ming Wong and Irene Oi-Lin Ng of Department of Pathology, Li Ka Shing Faculty Medicine, University of Hong Kong for useful advice and discussion. Peng Gao was a Cheng Yu Tung Fellow at the University of Hong Kong. The study was approved by the Ethics Committee of Shandong University.

Author contributions: Conception and design: Peng Gao. Collection and assembly of the data: Peng Gao, Ai-Yan Xing, Chao Gao, Duan-Bo Shi and Jian-Ping Zhang. Data analysis and interpretation: Peng Gao, Ai-Yan Xing, Geng-Yin Zhou and Ting-Guo Zhang. Manuscript writing: Peng Gao, Ai-Yan Xing, Geng-Yin Zhou and Shun-Li Zhang. Final approval of the manuscript: Peng Gao, Ai-Yan Xing, Geng-Yin Zhou, Ting-Guo Zhang, Chao Gao, Hong Li, Duan-Bo Shi and Jian-Ping Zhang.

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  1. P Gao and A-Y Xing: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Qilu Hospital, Shandong University, Shandong, PR China

    P Gao, A-Y Xing, G-Y Zhou, T-G Zhang, J-P Zhang & C Gao

  2. Department of Pathology, School of Medicine, Shandong University, Shandong, PR China

    H Li & D-B Shi

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  1. P Gao
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Correspondence to P Gao.

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Gao, P., Xing, AY., Zhou, GY. et al. The molecular mechanism of microRNA-145 to suppress invasion–metastasis cascade in gastric cancer. Oncogene 32, 491–501 (2013). https://doi.org/10.1038/onc.2012.61

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