Gankyrin Promotes Tumor Growth and Metastasis Through Activation of IL-6/STAT3 Signaling in Human Cholangiocarcinoma
Gankyrin Promotes Tumor Growth and Metastasis Through Activation of IL-6/STAT3 Signaling in Human Cholangiocarcinoma
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Gankyrin 通过激活人胆管癌中的 IL-6/STAT3 信号传导促进肿瘤生长和转移
DOI：
10.1002/hep.26705
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发表时间：
2014-03-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
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作者：
Zheng, Tongsen;Hong, Xuehui;Liu, Lianxin
虽然gankyrin参与了一些恶性肿瘤的致瘤性和转移，但其在胆管癌（CCA）中的作用尚不清楚。在本研究中，我们研究了gankyrin在人CCA组织和细胞系中的表达。在体内和体外实验中，研究了甘肽对CCA肿瘤生长和转移的影响。结果显示，gankyrin在CCA组织和细胞系中过表达。Gankyrin的表达与CCA的组织学分化、TNM分期和转移有关。多因素Cox分析显示，gankyrin是总生存的独立预后指标。Gankyrin过表达促进CCA细胞增殖、迁移和侵袭，而Gankyrin敲低抑制CCA肿瘤生长、转移，诱导rb依赖性衰老和G(1)期细胞周期阻滞。Gankyrin增加了转录信号传导激活因子3 （STAT3）的磷酸化，促进了p-STAT3的核易位。通过小干扰RNA （siRNA）或STAT3抑制剂抑制STAT3信号会干扰gankyrin介导的癌发生和转移，而已知的STAT3上游激活剂白介素(IL)-6可以恢复gankyrin沉默的CCA细胞的增殖和迁移。IL-6水平在gankyrin敲低的情况下降低，在gankyrin过表达的情况下升高。甘肽通过促进Rb磷酸化调节IL-6的表达；同时，IL-6处理增加了gankyrin的表达，提示IL-6在CCA中受gankyrin参与的正反馈回路调节。在异种移植实验中，gankyrin过表达加速了肿瘤的形成，增加了肿瘤的重量，而gankyrin敲低则表现出相反的效果。体内自发转移实验显示，gankyrin通过IL-6/STAT3信号通路促进CCA转移。结论：Gankyrin通过下调Rb蛋白激活IL-6/STAT3信号通路，在CCA的癌变转移中起重要作用。(肝脏病学59:935 2014;946)
Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G(1) phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. Conclusion: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein. (Hepatology 2014;59:935-946)