N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway
N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway
复制标题
N-myc下游调控基因2抑制人胆管癌进展并受白血病抑制因子/MicroRNA-181c负反馈通路调控
DOI：
10.1002/hep.28781
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发表时间：
2016-11-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Wang, Jiabei;Xie, Changming;Liu, Lianxin
越来越多的证据支持N-myc下游调控基因2 （NDRG2）在肿瘤发生中的作用。我们研究了NDRG2在人类胆管癌（CCA）进展中的作用和机制。本研究检测了NDRG2、microRNA (miR)-181c和白血病抑制因子（LIF）在人CCA及邻近非肿瘤组织中的表达。在体内和体外研究NDRG2对CCA肿瘤生长和转移的影响。研究了NDRG2/LIF/miR-181c信号通路在体内和体外胆管癌发生和转移中的作用。结果显示，与非肿瘤组织相比，人CCA组织的NDRG2水平降低，miR-181c和LIF水平升高。NDRG2在体外和体内均能抑制CCA细胞的增殖、耐药和转移。我们发现NDRG2是miR-181c的靶基因，NDRG2的下调归因于miR-181c在CCA中的过表达。此外，miR-181c可以被LIF治疗激活，而NDRG2可以通过破坏Smad、小母抗十足瘫复合体和LIF启动子之间的结合来抑制LIF转录。NDRG2的下调和miR-181c或LIF的过表达与CCA患者较差的总生存期（OS）显著相关。最后，我们发现NDRG2、miR-181c和LIF的联合表达是CCA患者预后的一个强有力的预测因子。结论：这些结果表明NDRG2与LIF/miR-181c之间的相互作用是调控胆管癌发生和转移的关键机制。我们的研究结果阐明了NDRG2介导的胆管癌发生和转移抑制的新途径，并提出了新的治疗靶点，包括NDRG2、LIF、miR-181c和转化生长因子β，在CCA的预防和治疗中。(肝脏病学64:1606 2016;1622)
Increasing evidence supports a role for N-myc downstream-regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)-181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR-181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR-181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR-181c, and the down-regulation of NDRG2 was attributed to miR-181c overexpression in CCA. Furthermore, miR-181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down-regulation of NDRG2 and overexpression of miR-181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR-181c, and LIF expression is a strong predictor of prognosis in CCA patients. Conclusion: These results establish the counteraction between NDRG2 and LIF/miR-181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2-mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR-181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606-1622)