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MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-04-01 , DOI: 10.1016/j.jhep.2019.11.021 Pei Tiemin 1 , Meng Fanzheng 1 , Xiao Peng 1 , Han Jihua 1 , Song Ruipeng 1 , Lan Yaliang 1 , Wang Yan 1 , Xue Junlin 1 , Lang Qingfu 1 , He Zhefeng 1 , Li Jian 1 , Guo Zihao 1 , Liu Guoxing 1 , Sun Boshi 1 , Zhao Ming 1 , Meng Qinghui 1 , Liang Desen 1 , Liu Lianxin 1
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-04-01 , DOI: 10.1016/j.jhep.2019.11.021 Pei Tiemin 1 , Meng Fanzheng 1 , Xiao Peng 1 , Han Jihua 1 , Song Ruipeng 1 , Lan Yaliang 1 , Wang Yan 1 , Xue Junlin 1 , Lang Qingfu 1 , He Zhefeng 1 , Li Jian 1 , Guo Zihao 1 , Liu Guoxing 1 , Sun Boshi 1 , Zhao Ming 1 , Meng Qinghui 1 , Liang Desen 1 , Liu Lianxin 1
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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.
中文翻译：
MUC13通过EGFR/PI3K/AKT通路促进肝内胆管癌进展
背景和目的 据报道，粘蛋白 13 (MUC13) 在人类恶性肿瘤中过度表达。然而，MUC13 在人肝内胆管癌 (iCCA) 中的临床病理学和生物学意义仍不清楚。本研究的目的是确定 MUC13 在 iCCA 进展中的作用。方法通过免疫组织化学、蛋白质印迹和实时PCR评估人iCCA样品中MUC13的表达水平。体外和体内实验用于评估MUC13对iCCA细胞生长和转移的影响。MUC13 和 EGFR/PI3K/AKT 信号之间的串扰通过分子方法进行分析。MUC13 的上游调节作用通过荧光素酶和 DNA 甲基化测定进行评估。结果 MUC13在人iCCA标本和iCCA细胞中过表达。MUC13 过表达与 iCCA 的临床病理特征（如血管侵犯和淋巴结转移）呈正相关，并且与较差的生存率独立相关。功能丧失和功能获得实验的结果表明，MUC13 的敲低减弱，而 MUC13 的过表达增强了 iCCA 细胞体外和体内的增殖、运动性和侵袭性。从机制上讲，我们发现 MUC13 介导的 iCCA 肿瘤转移需要磷脂酰肌醇 3-激酶-AKT 信号通路及其下游效应子，如金属蛋白酶 1 和基质金属肽酶 9 的组织抑制剂。MUC13 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/PI3K/AKT 信号通路。我们还发现 MUC13 直接受 miR-212-3p 调控，其下调与启动子区域异常的 CpG 高甲基化有关。结论 这些发现表明异常高甲基化诱导的 miR-212-3p 下调导致 iCCA 中 MUC13 的过表达，通过激活 EGFR/PI3K/AKT 信号通路导致转移。小结 粘蛋白 13 过表达与恶性肿瘤的发展有关，尽管尚未研究其在肝内胆管癌中的作用。在此，我们表明粘蛋白 13 在肝内胆管癌中起关键作用。
更新日期：2020-04-01
中文翻译：
MUC13通过EGFR/PI3K/AKT通路促进肝内胆管癌进展
背景和目的 据报道，粘蛋白 13 (MUC13) 在人类恶性肿瘤中过度表达。然而，MUC13 在人肝内胆管癌 (iCCA) 中的临床病理学和生物学意义仍不清楚。本研究的目的是确定 MUC13 在 iCCA 进展中的作用。方法通过免疫组织化学、蛋白质印迹和实时PCR评估人iCCA样品中MUC13的表达水平。体外和体内实验用于评估MUC13对iCCA细胞生长和转移的影响。MUC13 和 EGFR/PI3K/AKT 信号之间的串扰通过分子方法进行分析。MUC13 的上游调节作用通过荧光素酶和 DNA 甲基化测定进行评估。结果 MUC13在人iCCA标本和iCCA细胞中过表达。MUC13 过表达与 iCCA 的临床病理特征（如血管侵犯和淋巴结转移）呈正相关，并且与较差的生存率独立相关。功能丧失和功能获得实验的结果表明，MUC13 的敲低减弱，而 MUC13 的过表达增强了 iCCA 细胞体外和体内的增殖、运动性和侵袭性。从机制上讲，我们发现 MUC13 介导的 iCCA 肿瘤转移需要磷脂酰肌醇 3-激酶-AKT 信号通路及其下游效应子，如金属蛋白酶 1 和基质金属肽酶 9 的组织抑制剂。MUC13 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/PI3K/AKT 信号通路。我们还发现 MUC13 直接受 miR-212-3p 调控，其下调与启动子区域异常的 CpG 高甲基化有关。结论 这些发现表明异常高甲基化诱导的 miR-212-3p 下调导致 iCCA 中 MUC13 的过表达，通过激活 EGFR/PI3K/AKT 信号通路导致转移。小结 粘蛋白 13 过表达与恶性肿瘤的发展有关，尽管尚未研究其在肝内胆管癌中的作用。在此，我们表明粘蛋白 13 在肝内胆管癌中起关键作用。
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