Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

Journal of Translational Medicine

Research

Xuejiao Chen¹  Yuhua Shi¹  Yue Liu¹  Ziyi Wang²  Linfeng Sun²  Sheng Han²  Chenyu Jiao²  Yu Zhang²  Likalamu Pascalia Wikana²  Yuhao Xiao²  Nan Xia²  Wenjie Yu²  Liyong Pu²  Xiangdong Li²  Minhao Chen² 

[1] Department of General Surgery, Affiliated Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng, China;Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China;Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China;NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, China;

关键词: Hepatic ischemia reperfusion;    Tumor recurrence;    SGK1;    STAT3;    NRF2;   

DOI  :  10.1186/s12967-023-03977-z

 received in 2022-12-18, accepted in 2023-02-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLiver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis.MethodsColorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration.ResultsHepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR.ConclusionsOur study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.

【 授权许可】

CC BY   
© The Author(s) 2023

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