ETV4通过TGF-β信号传导调节糖酵解，从而促进胆管癌的进展。

ETV4 promotes the progression of cholangiocarcinoma by regulating glycolysis via the TGF-β signaling.

作者信息

Liu Fangfeng, Wang Qianchang, Wang Zhengjian, Zhang Shizhe, Ni Qingqiang, Chang Hong

机构信息

Department of Hepatobiliary surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.

出版信息

Transl Oncol. 2024 Sep;47:102035. doi: 10.1016/j.tranon.2024.102035. Epub 2024 Jun 14.

DOI:10.1016/j.tranon.2024.102035

PMID:38878613

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11225894/

Abstract

BACKGROUND

Considerable studies show that ETS variant 4 (ETV4) plays an important roles in multitudinous tumor. This study investigated its function in cholangiocarcinoma (CCA) progression and revealed the underlying mechanisms.

METHODS

The expression of ETV4 in CCA was evaluated using TCGA database and the single-cell analysis based on GSE189903 dataset. ETV4 expression in CCA human specimens was detected by reverse transcription-quantitative PCR, immunohistochemistry, and western blot. Cell Counting Kit-8, EdU, colony formation, wound healing, and Transwell assays were used to analyze the effects of ETV4. Extracellular acidification rate, oxygen consumption rate, glucose uptake, and lactate production were used to measure glycolysis in CAA cells. Western blot was performed to explore glycolysis-related proteins. Tumor growth was evaluated in mice xenograft tumors.

RESULTS

ETV4 was up-regulated in CCA epithelial cells. The high-expression of ETV4 was associated with poor prognosis of patients with CCA. ETV4 overexpression enhanced the proliferation, migration, invasion, and glycolysis of CCA cells; ETV4 silencing led to the contrary effects. Mechanistically, ETV4 activates TGF-β/Smad2/3 signaling pathway. In mice xenograft mode, ETV4 silencing inhibits the tumor growth, the expression of glycolysis-related proteins and TGF-β/Smad2/3 pathway proteins.

CONCLUSIONS

ETV4 functions as an essential factor in the roles of TGF-β1 in CCA cells, and may be a promising target for TGF-β1-mediated CCA progression.

摘要

背景

大量研究表明，ETS变异体4（ETV4）在众多肿瘤中发挥重要作用。本研究调查了其在胆管癌（CCA）进展中的作用，并揭示了潜在机制。

方法

使用TCGA数据库和基于GSE189903数据集的单细胞分析评估ETV4在CCA中的表达。通过逆转录定量PCR、免疫组织化学和蛋白质印迹法检测CCA人体标本中ETV4的表达。使用细胞计数试剂盒-8、EdU、集落形成、伤口愈合和Transwell实验分析ETV4的作用。使用细胞外酸化率、氧消耗率、葡萄糖摄取和乳酸生成来测量CAA细胞中的糖酵解。进行蛋白质印迹以探索糖酵解相关蛋白。在小鼠异种移植瘤中评估肿瘤生长。

结果

ETV4在CCA上皮细胞中上调。ETV4的高表达与CCA患者的不良预后相关。ETV4过表达增强了CCA细胞的增殖、迁移、侵袭和糖酵解；ETV4沉默则产生相反的效果。机制上，ETV4激活TGF-β/Smad2/3信号通路。在小鼠异种移植模型中，ETV4沉默抑制肿瘤生长、糖酵解相关蛋白和TGF-β/Smad2/3通路蛋白的表达。