MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways
MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways
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MUC13通过EGFR/PI3K/AKT途径促进肝内胆管癌进展
DOI：
10.1016/j.jhep.2019.11.021
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发表时间：
2020-04-01
影响因子：
25.7
通讯作者：
Liu Lianxin
中科院分区：
文献类型：
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作者：
Pei Tiemin;Meng Fanzheng;Liu Lianxin
背景与目的：据报道，粘蛋白13（MUC 13）在人类恶性肿瘤中过表达。然而，MUC 13在人肝内胆管癌（iCCA）中的临床病理学和生物学意义尚不清楚。本研究的目的是确定MUC 13在iCCA的进展中的作用。方法：MUC 13在人iCCA样本中的表达水平通过免疫组织化学、western blot和实时PCR进行评估。使用体外和体内实验来评估MUC 13对iCCA细胞生长和转移的影响。通过分子方法分析MUC 13与EGFR/PI 3 K/AKT信号传导之间的串扰。结果：MUC 13在人iCCA标本和iCCA细胞中均过表达，并与正常对照组比较，差异有统计学意义（P < 0. 05）。MUC 13过表达与iCCA的临床病理特征（例如血管侵袭和淋巴结转移）正相关，并且与生存率低独立相关。功能丧失和功能获得实验的结果表明，MUC 13的敲低减弱，而MUC 13的过表达增强，iCCA细胞在体外和体内的增殖，运动性和侵袭性。从机制上讲，我们发现磷脂酰肌醇3-激酶-AKT信号通路及其下游效应物，如金属蛋白酶组织抑制剂1和基质金属肽酶9，是MUC 13介导的iCCA肿瘤转移所必需的。MUC 13与表皮生长因子受体（EGFR）相互作用，随后通过促进EGFR二聚化和阻止EGFR内化来激活EGFR/PI 3 K/AKT信号通路。结论：miR-212 - 3 p异常甲基化诱导的MUC 13基因表达下调可导致iCCA中MUC 13的过度表达，并通过激活EGFR/PI 3 K/AKT信号通路导致肿瘤转移。敷设总结：粘蛋白13过表达与恶性肿瘤的发生有关，但其在肝内胆管癌中的作用尚未研究。在此，我们发现粘蛋白13在肝内胆管癌中起着关键作用。粘蛋白13作为预后标志物和治疗靶点都具有治疗价值。(C)2019年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA.Methods: Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays.Results: MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/ PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area.Conclusions: These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. Lay summary: Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.