肝缺血再灌注激活的肝细胞 SGK1 通过 IL-6/STAT3 促进肝转移的复发。
Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3.
机构信息
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
出版信息
J Transl Med. 2023 Feb 14;21(1):121. doi: 10.1186/s12967-023-03977-z.
BACKGROUND
Liver 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.
METHODS
Colorectal 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.
RESULTS
Hepatocyte 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.
CONCLUSIONS
Our 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.
背景
肝转移是结直肠癌（CRC）患者死亡的主要原因。肝转移灶切除术提高了结直肠癌肝转移（CRLM）患者的长期生存率。然而，许多患者在初始肝切除术后经历 CRLM 复发。作为肝外科不可避免的病理生理过程，肝缺血再灌注（IR）损伤增加了肿瘤复发和转移的风险。
方法
构建了结直肠肝转移（CRLM）小鼠模型和小鼠肝部分热缺血模型。检测细胞或组织中脂质过氧化水平。通过 Western Blot、qPCR、elisa、免疫荧光、免疫组化、扫描电子显微镜、流式细胞术分析等方法，评价肝缺血再灌注（IR）背景下 CRLM 复发过程中多个信号通路的变化，包括 SGK1/IL-6/STAT3、中性粒细胞胞外诱捕网（NETs）形成、多形核髓系来源抑制细胞（PMN-MDSC）浸润。
结果
肝缺血再灌注损伤导致肝细胞血清/糖皮质激素调节激酶 1（SGK1）激活，传递肝细胞 STAT3 磷酸化和血清淀粉样蛋白 A（SAA）过度激活信号，在 CRLM-IR 小鼠中，这种调节依赖于 SGK 激活的白细胞介素 6（IL-6）自分泌。与仅靶向肝细胞 SGK1 相比，SGK1 抑制剂 GSK-650394 的给药进一步减少了 ERK 相关的中性粒细胞胞外诱捕网（NETs）形成和多形核髓系来源抑制细胞（PMN-MDSC）浸润，从而缓解了 IR 背景下的 CRLM。
结论
本研究表明，肝细胞和免疫细胞 SGK1 协同促进肝 IR 应激后术后 CRLM 的复发，并确定 SGK1 是一个可能改善术后 CRLM 复发的转化靶点。
Zotero 插件