Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma.

IF 3.3 3区 医学 Q2 ONCOLOGY
Yutaro Hori, Tomoaki Yoh, Hiroto Nishino, Keisuke Okura, Makoto Kurimoto, Yuichi Takamatsu, Motohiko Satoh, Takahiro Nishio, Yukinori Koyama, Takamichi Ishii, Keiko Iwaisako, Satoru Seo, Etsuro Hatano
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Abstract

The role of the ferroptosis-related gene glutathione peroxidase 4 (GPX4) in oncology has been extensively investigated. However, the clinical implications of GPX4 in patients with intrahepatic cholangiocarcinoma (ICC) remain unknown. This study aimed to evaluate the prognostic impact of GPX4 and its underlying molecular mechanisms in patients with ICC. Fifty-seven patients who underwent surgical resection for ICC between 2010 and 2017 were retrospectively analyzed. Based on the immunohistochemistry, patients were divided into GPX4 high (n = 15) and low (n = 42) groups, and clinical outcomes were assessed. Furthermore, the roles of GPX4 in cell proliferation, migration and gene expression were analyzed in ICC cell lines in vitro and in vivo. The results from clinical study showed that GPX4 high group showed significant associations with high SUVmax on 18F-fluorodeoxyglucose-positron emission tomography (≥8.0, P = 0.017), multiple tumors (P = 0.004), and showed glucose transporter 1 (GLUT1) high expression with a trend toward significance (P = 0.053). Overall and recurrence-free survival in the GPX4 high expression group were significantly worse than those in the GPX4 low expression group (P = 0.038 and P < 0.001, respectively). In the experimental study, inhibition of GPX4 attenuated cell proliferation and migration in ICC cell lines. Inhibition of GPX4 also decreased the expression of glucose metabolism-related genes, such as GLUT1 or HIF1α. Mechanistically, these molecular changes are regulated in Akt-mechanistic targets of rapamycin axis. In conclusion, this study suggested the pivotal value of GPX4 serving as a prognostic marker for patients with ICC. Furthermore, GPX4 can mediate glucose metabolism of ICC.

铁变态相关基因谷胱甘肽过氧化物酶 4 通过 Akt-mTOR 轴促进肝内胆管癌的葡萄糖代谢重编程
人们已经广泛研究了与铁变态反应相关的基因谷胱甘肽过氧化物酶 4(GPX4)在肿瘤学中的作用。然而,GPX4对肝内胆管癌(ICC)患者的临床影响仍然未知。本研究旨在评估 GPX4 对 ICC 患者预后的影响及其潜在的分子机制。研究人员对2010年至2017年间接受手术切除的57例ICC患者进行了回顾性分析。根据免疫组化结果,将患者分为GPX4高(n=15)和低(n=42)两组,并对临床结果进行了评估。此外,还分析了GPX4在体外和体内ICC细胞系中细胞增殖、迁移和基因表达的作用。临床研究结果显示,GPX4高组与18F-FDG-PET SUVmax高(≥ 8.0,p=0.017)、多肿瘤(p=0.004)有显著相关性,并显示GLUT1高表达,且有显著性趋势(p=0.053)。GPX4 高表达组的总生存率和无复发生存率明显低于 GPX4 低表达组(p=0.038 和 p
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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