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Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis

Oncogene volume 33, pages 1287–1296 (2014)Cite this article

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Abstract

Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.

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Acknowledgements

We thank Dr Eva Hernando for providing the miR-182 overexpression plasmid. The study was funded by the grants from the Ministry of Science and Technology of China (2011CB510105, 2012ZX09506-001-005), National Natural Science Foundation of China (81071754,81222032), Chinese Academy of Sciences (2009OHTP08, KSCX2-YW-R-192) and the Shanghai Pujiang Talent Program (10PJ1411600).

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  1. R Lei and J Tang: These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China

    R Lei, X Zhuang, G Li, J Yu, Y Liang & G Hu

  2. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China

    J Tang

  3. State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China

    J Tang, R Deng & H-Y Wang

  4. Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China

    J Xiao

  5. Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, China

    Q Yang

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Lei, R., Tang, J., Zhuang, X. et al. Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis. Oncogene 33, 1287–1296 (2014). https://doi.org/10.1038/onc.2013.65

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