Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma.
Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma.
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DOI：
10.1111/cas.13341
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发表时间：
2017-10
期刊：
影响因子：
5.7
通讯作者：
Kudo M
中科院分区：
文献类型：
--
作者：
Sakurai T;Yada N;Hagiwara S;Arizumi T;Minaga K;Kamata K;Takenaka M;Minami Y;Watanabe T;Nishida N;Kudo M
大多数肝细胞癌（HCC）是由于慢性肝脏炎症而发展的。我们已经证明，癌蛋白gankyrin对于炎症诱导的结肠肿瘤发生至关重要。虽然Gankyrin的体外功能是众所周知的，但其在体内的作用仍有待阐明。我们研究了肝实质细胞特异性gankyrin消融（Alb‐Cre;gankyrin f/f）和肝实质和非实质细胞中gankyrin缺失（Mx 1 ‐Cre;gankyrin f/f）的小鼠肿瘤微环境中gankyrin的作用。Gankyrin上调肿瘤细胞血管内皮生长因子表达。Gankyrin与主要在肝非实质细胞中表达的含Src同源2结构域的蛋白酪氨酸磷酸酶-1（SHP-1）结合，导致信号转导和转录激活因子3（STAT 3）的磷酸化和激活。Gankyrin在非实质细胞中缺乏，但在实质细胞中不缺乏，降低了STAT 3活性、白细胞介素（IL）-6产生和癌症干细胞标志物（Bmi 1和上皮细胞粘附分子[EpCAM]）表达，导致致瘤潜力减弱。慢性炎症增强人类肝脏中Gankyrin的表达。肿瘤微环境中Gankyrin的表达与接受索拉非尼治疗的HCC患者的无进展生存期呈负相关。因此，Gankyrin似乎在肿瘤微环境中发挥关键的致癌功能，并可能成为开发针对HCC的治疗和预防策略的潜在靶点。
Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation‐induced tumorigenesis in the colon. Although the in vitro function of gankyrin is well known, its role in vivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell‐specific gankyrin ablation (Alb‐Cre;gankyrin f/f) and gankyrin deletion both in liver parenchymal and non‐parenchymal cells (Mx1‐Cre;gankyrin f/f). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP‐1), mainly expressed in liver non‐parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non‐parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)‐6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression‐free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.
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影响因子：
5.7
作者：
Sakurai T;Yada N;Watanabe T;Arizumi T;Hagiwara S;Ueshima K;Nishida N;Fujita J;Kudo M
通讯作者：
Kudo M
影响因子：
4.9
作者：
Adachi T;Sakurai T;Kashida H;Mine H;Hagiwara S;Matsui S;Yoshida K;Nishida N;Watanabe T;Itoh K;Fujita J;Kudo M
通讯作者：
Kudo M
影响因子：
50.3
作者：
Sakurai T;He G;Matsuzawa A;Yu GY;Maeda S;Hardiman G;Karin M
通讯作者：
Karin M
影响因子：
50.3
作者：
Gargiulo, Gaetano;Cesaroni, Matteo;van Lohuizen, Maarten
通讯作者：
van Lohuizen, Maarten
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi