HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET.
HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET.
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HGF介导的ETV1升高通过上调PTK2和c-MET促进肝细胞癌转移
DOI：
10.1186/s13046-022-02475-2
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发表时间：
2022-09-16
影响因子：
11.3
通讯作者：
Xia, Limin
中科院分区：
文献类型：
--
作者：
Zhang, Tongyue;Wang, Yijun;Xie, Meng;Ji, Xiaoyu;Luo, Xiangyuan;Chen, Xiaoping;Zhang, Bixiang;Liu, Danfei;Feng, Yangyang;Sun, Mengyu;Huang, Wenjie;Xia, Limin
关键词：
背景转移是肝细胞癌（HCC）患者死亡的主要决定因素。剖析促进这种恶性特征的关键分子介质可能有助于产生新的治疗见解。在这里，我们调查的作用E-26-transformation-specific变体1（ETV 1），E-26-transformation-specific（ETS）家族的成员，在HCC transferation.MethodsThe临床意义ETV 1及其靶基因在两个独立的队列肝癌患者接受根治性切除的Kaplan-Meier分析和多变量考克斯比例风险模型进行了评估。荧光素酶报告基因分析和染色质免疫沉淀分析检测ETV 1对目的基因启动子的转录调控。结果ETV 1在人肝癌组织中的表达明显增高，在肝癌组织中的表达与肿瘤侵袭转移密切相关。ETV 1表达增高与HCC的恶性生物学特性及预后不良有关。ETV 1在体内外均能促进肝癌细胞的侵袭和转移。ETV 1通过上调转移相关基因PTK 2和MET的表达促进肝癌转移，下调PTK 2和c-MET的表达可降低ETV 1介导的肝癌转移。肝细胞生长因子（HGF）通过激活c-MET-ERK 1/2-ELK 1通路上调ETV 1的表达。值得注意的是，在两个独立的队列中，ETV 1/PTK 2或ETV 1/c-MET共表达阳性的患者预后较差。PTK 2抑制剂defactinib和c-MET抑制剂capmatinib联合应用可显著抑制ETV 1诱导的肝癌转移。结论ETV 1在肝癌中的功能和预后作用，揭示了HGF-ERK 1/2-ETV 1-c-MET的正反馈环。靶向这一途径可能为ETV 1过表达的HCC提供潜在的治疗干预。
BackgroundMetastasis is a major determinant of death in patients with hepatocellular carcinoma (HCC). Dissecting key molecular mediators that promote this malignant feature may help yield novel therapeutic insights. Here, we investigated the role of E-twenty-six transformation-specific variant 1 (ETV1), a member of the E-twenty-six transformation-specific (ETS) family, in HCC metastasis.MethodsThe clinical significance of ETV1 and its target genes in two independent cohorts of HCC patients who underwent curative resection were assessed by Kaplan–Meier analysis and Multivariate Cox proportional hazards model. Luciferase reporter assay and chromatin immunoprecipitation assay were used to detect the transcriptional regulation of target gene promoters by ETV1. The effect of ETV1 on invasiveness and metastasis of HCC were detected by transwell assays and the orthotopically metastatic model.ResultsETV1 expression was frequently elevated in human HCC specimens. Increased ETV1 expression was associated with the malignant biological characteristics and poor prognosis of HCC patients. ETV1 facilitated invasion and metastasis of HCC cells in vitro and in vivo. Mechanistically, ETV1 promoted HCC metastasis via upregulating metastasis-related genes, includingprotein tyrosine kinase 2(PTK2) andMET.Down-regulated the expression of PTK2 or tyrosine protein kinase Met (c-MET) decreased ETV1-mediated HCC metastasis. Hepatocyte growth factor (HGF) upregulated ETV1 expression through activating c-MET-ERK1/2-ELK1 pathway. Notably, in two independent cohorts, patients with positive coexpression of ETV1/PTK2 or ETV1/c-MET had worse prognosis. Furthermore, the combination of PTK2 inhibitor defactinib and c-MET inhibitor capmatinib significantly suppressed HCC metastasis induced by ETV1.ConclusionThis study uncovers functional and prognostic roles for ETV1 in HCC and exposes a positive feedback loop of HGF-ERK1/2-ETV1-c-MET. Targeting this pathway may provide a potential therapeutic intervention for ETV1-overexpressing HCC.
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DOI：
10.1002/hep.29496
发表时间：
2018-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Bouattour M;Raymond E;Qin S;Cheng AL;Stammberger U;Locatelli G;Faivre S
通讯作者：
Faivre S
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
29.4
作者：
Heeg S;Das KK;Reichert M;Bakir B;Takano S;Caspers J;Aiello NM;Wu K;Neesse A;Maitra A;Iacobuzio-Donahue CA;Hicks P;Rustgi AK
通讯作者：
Rustgi AK
影响因子：
15.9
作者：
Kaposi-Novak, Pal;Lee, Ju-Seog;Thorgeirsson, Snorri S.
通讯作者：
Thorgeirsson, Snorri S.
影响因子：
45.3
作者：
Gordan, John D.;Kennedy, Erin B.;Rose, Michal G.
通讯作者：
Rose, Michal G.