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微小RNA-200b/200c/429亚家族负向调控Rho/ROCK信号通路以抑制肝细胞癌转移。

MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis.

作者信息

Wong Chun-Ming, Wei Lai, Au Sandy Leung-Kuen, Fan Dorothy Ngo-Yin, Zhou Yuan, Tsang Felice Ho-Ching, Law Cheuk-Ting, Lee Joyce Man-Fong, He Xianghuo, Shi Jue, Wong Carmen Chak-Lui, Ng Irene Oi-Lin

机构信息

Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Department of Physics and Department of Biology, Centre for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.

出版信息

Oncotarget. 2015 May 30;6(15):13658-70. doi: 10.18632/oncotarget.3700.

DOI:10.18632/oncotarget.3700
PMID:25909223
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4537040/
Abstract

MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.

摘要

微小RNA-200家族是上皮-间质转化的重要调节因子，与人类癌症发生有关。然而，它们在人类癌症中的表达和功能仍存在争议。在本文所述的研究中，我们发现微小RNA-200家族成员在肝细胞癌（HCC）中经常下调。虽然微小RNA-200家族的所有五个成员都能抑制HCC细胞系中锌指E盒结合蛋白1/2（ZEB1/2）的表达，但我们发现只有微小RNA-200b/200c/429亚家族（而非微小RNA-200a/141亚家族）的过表达会导致HCC细胞迁移受阻。进一步研究确定了RhoA和Rho相关卷曲螺旋蛋白激酶2（ROCK2）是微小RNA-200b/200c/429亚家族的特定下游靶点。我们证明，微小RNA-200b/200c/429亚家族通过调节Rho/ROCK介导的细胞骨架重组和细胞-基质黏附来抑制HCC细胞迁移。在体内原位肝移植模型中，重新表达微小RNA-200b可显著抑制HCC细胞的肺转移。总之，我们的研究结果确定了微小RNA-200b/200c/429亚家族是人类HCC中的转移抑制性微小RNA，并突出了微小RNA-200家族成员之间的功能差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/c6efe2126187/oncotarget-06-13658-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/2de215403822/oncotarget-06-13658-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/68acc13f0e03/oncotarget-06-13658-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/e287afb8c1b5/oncotarget-06-13658-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/ca72f25df2ca/oncotarget-06-13658-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/af0059325d9b/oncotarget-06-13658-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/c6efe2126187/oncotarget-06-13658-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/2de215403822/oncotarget-06-13658-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/68acc13f0e03/oncotarget-06-13658-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/e287afb8c1b5/oncotarget-06-13658-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/ca72f25df2ca/oncotarget-06-13658-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/af0059325d9b/oncotarget-06-13658-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc3d/4537040/c6efe2126187/oncotarget-06-13658-g006.jpg

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