Direct targeting of SUZ12/ROCK2 by miR-200b/c inhibits cholangiocarcinoma tumourigenesis and metastasis.
Direct targeting of SUZ12/ROCK2 by miR-200b/c inhibits cholangiocarcinoma tumourigenesis and metastasis.
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miR-200b/c直接靶向SUZ12/ROCK2抑制胆管癌肿瘤发生和转移
DOI：
10.1038/bjc.2013.655
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发表时间：
2013-12-10
影响因子：
8.8
通讯作者：
Qin, R.
中科院分区：
文献类型：
--
作者：
Peng, F.;Jiang, J.;Yu, Y.;Tian, R.;Guo, X.;Li, X.;Shen, M.;Xu, M.;Zhu, F.;Shi, C.;Hu, J.;Wang, M.;Qin, R.
胆管癌的多药耐药和远处转移导致术后复发率高，长期生存率低。研究表明，miR-200的异位表达抑制肿瘤的多药耐药和转移。然而，miR-200在胆管癌中的表达和功能尚未被描述。在本研究中，我们通过微阵列分析鉴定了胆管癌组织中表达异常的microRNAs（miRNAs，miR），随后的实时PCR和北方印迹分析验证了候选miR的表达。我们进行了功能分析，并研究了miR-200 b/c表达与胆管癌细胞特性之间的关系。采用双荧光素酶法检测miRNAs对靶基因3′-UTR的影响，并通过siRNA转染，通过Western blotting鉴定下游通路，验证目的基因的功能。我们发现四个miR-200家族成员（miR-200 a/B/c/429）的表达显著下调，进而证实异位miR-200 B/200 c在体外和体内均抑制胆管癌细胞的迁移和侵袭。我们发现miR-200 b/c影响胆管癌细胞的肿瘤发生，包括其肿瘤起始能力、球体形成和耐药性。我们进一步发现，miR-200 b/c通过直接靶向rho激酶2调节迁移和侵袭能力，并通过直接靶向SUZ 12（多梳阻遏物复合物的亚基）调节致瘤特性。我们的研究表明miR-200 b/c在胆管癌的发生和转移能力的调节中具有关键作用，并揭示了可能的潜在机制。
The multidrug resistance and distant metastasis of cholangiocarcinoma result in high postoperative recurrence and low long-term survival rates. It has been demonstrated that the ectopic expression of miR-200 suppresses the multidrug resistance and metastasis of cancer. However, the expression and function of miR-200 in cholangiocarcinoma has not yet been described. In this study, we identified dysregulated microRNAs (miRNAs, miR) in cholangiocarcinoma tissue by microarray analysis, and subsequent real-time PCR and northern blot analyses validated the expression of candidate miR. We performed functional analyses and investigated the relationship between miR-200b/c expression and the properties of cholangiocarcinoma cells. A dual luciferase assay was applied to examine the effect of miRNAs on the 3′-UTR of target genes, and we demonstrated the function of the target gene by siRNA transfection identifying the downstream pathway via western blotting. We found significantly downregulated expression of four miR-200 family members (miR-200a/b/c/429) and then confirmed that ectopic miR-200b/200c inhibits the migration and invasion of cholangiocarcinoma cells both in vitro and in vivo. We found that miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance. We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex). Our study shows that miR-200b/c has a critical role in the regulation of the tumorigenic and metastatic capacity of cholangiocarcinoma and reveals the probable underlying mechanisms.
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影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
10.5
作者：
Park, Sun-Mi;Gaur, Arti B.;Peter, Marcus E.
通讯作者：
Peter, Marcus E.
影响因子：
64.5
作者：
Karres, Janina S.;Hilgers, Valerie;Cohen, Stephen M.
通讯作者：
Cohen, Stephen M.
影响因子：
23.9
作者：
Hermann, Patrick C.;Huber, Stephan L.;Heeschen, Christopher
通讯作者：
Heeschen, Christopher