TGR5 promotes cholangiocarcinoma by interacting with mortalin
TGR5 promotes cholangiocarcinoma by interacting with mortalin
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TGR5通过与mortalin相互作用促进胆管癌
DOI：
10.1016/j.yexcr.2020.111855
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发表时间：
2020-04-15
影响因子：
3.7
通讯作者：
Jiang, Hui-Qing
中科院分区：
文献类型：
--
作者：
Li, Ai-Di;Xie, Xiao-Li;Jiang, Hui-Qing
武田-G-蛋白-受体-5(TGR5)是胆汁酸激活的G-蛋白偶联受体，而死亡蛋白是HSP70家族的多能伴侣。本研究采用免疫组织化学方法检测TGR5在肝外胆管细胞癌(ECC)组织中的表达，并比较TGR5在ECC组织和癌旁组织中的表达。为观察TGR5在体外对人肝内胆管癌细胞(ICC)和人肝外胆管癌细胞(ECC)的增殖、凋亡和迁移等生物学行为的影响，对人肝内胆管癌细胞系RBE和人肝外胆管癌细胞系QBC-939进行TGR5过表达和下调。建立体内异种移植模型，探讨TGR5在CC生长中的作用。用免疫沉淀光谱方法筛选与TGR5相互作用的蛋白质，并下调鉴定的蛋白质以研究其对CC生长的贡献。本研究表明，TGR5在CC组织中高表达，TGR5的高表达可能提示CC的恶性程度较高。此外，TGR5还促进CC细胞的增殖、迁移和抗凋亡。TGR5促进体内CC生长。此外，TGR5与mortalin结合并调节CC细胞系中mortalin的表达。Mortalin参与TGR5诱导的CC细胞增殖。总之，根据TGR5对CC患者恶性程度的影响，TGR5具有临床意义。Mortalin可能是受TGR5调控的下游成分，TGR5至少部分地通过与mortalin相互作用并上调其表达来促进胆管癌细胞的发生。TGR5和mortalin都是阳性调节因子，可能成为CC的潜在治疗靶点。
Takeda-G-protein-receptor-5 (TGR5) is a G-protein-coupled receptor (GPCR) activated by bile acids, and mortalin is a multipotent chaperone of the HSP70 family. In the present study, TGR5 was detected by immunohistochemistry (IHC) in extrahepatic cholangiocarcinoma (ECC) specimens, and TGR5 expression in ECC tissues and adjacent tissues was compared. In vitro TGR5 was overexpressed and knocked down in human intrahepatic cholangiocarcinoma (ICC) cell line RBE and human extrahepatic cholangiocarcinoma (ECC) cell line QBC-939 to observe its effects on the biological behavior of cholangiocarcinoma (CC) cells, including proliferation, apoptosis and migration. In vivo xenograft model was constructed to explore the role of TGR5 in CC growth. Proteins that interacted with TGR5 were screened using an immunoprecipitation spectrometry approach, and the identified protein was down-regulated to investigate its contribution to CC growth. The present study demonstrated that TGR5 is highly expressed in CC tissues, and strong TGR5 expression may indicate high malignancy in CC. Furthermore, TGR5 promotes CC cell proliferation, migration, and apoptosis resistance. TGR5 boosts CC growth in vivo. In addition, TGR5 combines with mortalin and regulates mortalin expression in the CC cell line. Mortalin participates in the TGR5-induced increase in CC cell proliferation. In conclusion, TGR5 is of clinical significance based on its implications for the degree of malignancy in patients with CC. Mortalin may be a downstream component regulated by TGR5, and TGR5 promotes cholangiocarcinoma at least partially by interacting with mortalin and upregulating its expression. Both TGR5 and mortalin are positive regulators, and may serve as potential therapeutic targets for CC.