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Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1

Oncogene volume 33, pages 514–524 (2014)Cite this article

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Abstract

Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.

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Acknowledgements

The authors would like to thank Professor Zude Xu from Department of Pathology, Huashan Hospital, Fudan University, Shanghai for providing human pancreatic cancer samples. This study was supported by National Science Fundation of China (81001061); Shanghai Nature Science Fund, Shanghai, China (09ZR1406800); Doctoral Programs Foundation of Ministry of Education of China (20090071120076); Shanghai Science and Technology Committee Rising-Star Program (11QA1401300); and Medical Talents Training Program of Health Bureau of Shanghai (XYQ2011008) and 985 research grants.

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Authors and Affiliations

  1. Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    P Wang, L Chen, J Zhang, H Chen, K Wang, Z Chen, Z Meng & L Liu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    P Wang, L Chen, J Zhang, H Chen, K Wang, Z Chen, Z Meng & L Liu

  3. Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

    J Fan

  4. Central Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China

    J Luo

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  1. P Wang
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Correspondence to Z Chen, Z Meng or L Liu.

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Wang, P., Chen, L., Zhang, J. et al. Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene 33, 514–524 (2014). https://doi.org/10.1038/onc.2012.598

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