Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of β-Catenin.
Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of β-Catenin.
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骨桥蛋白通过招募 MAPK1 和介导 β-Catenin Ser675 磷酸化促进肝内胆管癌的转移。
DOI：
10.1038/s41419-017-0226-x
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Qin LX
中科院分区：
文献类型：
--
作者：
Zheng Y;Zhou C;Yu XX;Wu C;Jia HL;Gao XM;Yang JM;Wang CQ;Luo Q;Zhu Y;Zhang Y;Wei JW;Sheng YY;Dong QZ;Qin LX
近几十年来，肝内胆管癌（ICC）的发病率和死亡率在全球范围内呈上升趋势。骨桥蛋白（Osteopontin， OPN）在肿瘤转移中起重要作用，但其在ICC中的作用机制尚不清楚。在本研究中，我们发现ICC患者血浆和肿瘤组织中OPN水平均升高，这与较短的总生存期（OS）和根治性切除后肿瘤复发率高密切相关。功能获得和功能丧失的研究表明，OPN可以促进ICC的生长和转移。OPN选择性地与β-Catenin相互作用，敲低β-Catenin可消除OPN诱导的作用。OPN募集MAPK1，激活MEK-MAPK1通路，介导β-Catenin的S675磷酸化和细胞核聚集，诱导Wnt信号通路的激活。此外，在ICC组织中发现OPN与β-Catenin之间存在显著相关性。OPN、β-Catenin及其联合是ICC患者独立的预后指标。综上所述，OPN通过募集MAPK1和激活Wnt/β-Catenin通路来促进ICC的进展，可以作为ICC的一种新的预后标志物和治疗靶点。
The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide in recent decades. Osteopontin (OPN) plays an important role in cancer metastasis, but its functional mechanism in ICC is not clear yet. In this study, we found that OPN level was elevated both in plasma and tumor tissues of ICC patients, which was closely related to a shorter overall survival (OS) and high probability of tumor relapse after curative resection. The gain- and loss-of-function studies determined that OPN could promote ICC growth and metastasis. OPN selectively interacted with β-Catenin and knockdown of β-Catenin abrogated the effects induced by OPN. OPN recruited MAPK1 and activated MEK–MAPK1 pathway to mediate the S675 phosphorylation of β-Catenin and nucleus accumulation, which induced the activation of Wnt signaling. Moreover, a significant correlation between OPN and β-Catenin was found in ICC tissues. OPN, β-Catenin, and their combination were independent prognostic indicator for ICC patients. In conclusion, OPN promotes ICC progression through recruiting MAPK1 and activating the Wnt/β-Catenin pathway and can serve as a novel prognostic marker and therapeutic target for ICC.
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影响因子：
9
作者：
Chu Q;Huang H;Huang T;Cao L;Peng L;Shi S;Zheng L;Xu L;Zhang S;Huang J;Li X;Qian C;Huang B
通讯作者：
Huang B
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29.4
作者：
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通讯作者：
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作者：
Pietras, Alexander;Katz, Amanda M.;Ekstroem, Elin J.;Wee, Boyoung;Halliday, John J.;Pitter, Kenneth L.;Werbeck, Jillian L.;Amankulor, Nduka M.;Huse, Jason T.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
10.5
作者：
Brembeck, FH;Schwarz-Romond, T;Birchmeier, W
通讯作者：
Birchmeier, W
影响因子：
13.5
作者：
Dong, Qiong-Zhu;Zhang, Xiao-Fei;Qin, Lun-Xiu
通讯作者：
Qin, Lun-Xiu