RRC ID 78424
Author Hori Y, Yoh T, Nishino H, Okura K, Kurimoto M, Takamatsu Y, Satoh M, Nishio T, Koyama Y, Ishii T, Iwaisako K, Seo S, Hatano E.
Title Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma.
Journal Carcinogenesis
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.
Volume 45(3)
Pages 119-130
Published 2024-3-11
DOI 10.1093/carcin/bgad094
PII 7484495
PMID 38123365
MeSH Bile Duct Neoplasms* / pathology Bile Ducts, Intrahepatic / pathology Cholangiocarcinoma* / genetics Cholangiocarcinoma* / metabolism Cholangiocarcinoma* / surgery Ferroptosis* / genetics Glucose Glucose Transporter Type 1 / genetics Humans Phospholipid Hydroperoxide Glutathione Peroxidase / genetics Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Retrospective Studies TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism
Human and Animal Cells HuH-7(RCB1366)