BACKGROUND Ischemia reperfusion injury (IRI) has been shown to increase the risk of tumor recurrence after liver surgery. Also, nonalcoholic fatty liver disease (NAFLD) is associated with increased HCC recurrence. ALOX12-12-HETE pathway is activated both in liver IRI and NASH. Also, ALOX12-12-HETE has been shown to mediate tumorigenesis and progression. Therefore, our study aims to investigate whether the ALOX12-12-HETE-GPR31 pathway involved in IRI induced HCC recurrence in NAFLD. METHODS HCC mouse model was used to mimic the HCC recurrence in NAFLD. Western Blot, qPCR, Elisa and Immunofluorescence analysis were conducted to evaluate the changes of multiple signaling pathways during HCC recurrence, including ALOX12-12-HETE axis, EMT, MMPs and PI3K/AKT/NF-κB signaling pathway. We also measured the expression and functional changes of GPR31 by siRNA. RESULTS ALOX12-12-HETE pathway was activated in liver IRI and its activation was further enhanced in NAFLD, which induced more severe HCC recurrence in fatty livers than normal livers. Inhibition of ALOX12-12-HETE by ML355 reduced the HCC recurrence in fatty livers. In vitro studies showed that 12-HETE increased the expression of GPR31 and induced epithelial-mesenchymal transition (EMT) and matrix metalloprotein (MMPs) by activating PI3K/AKT/NF-κB pathway. Furthermore, knockdown of GPR31 in cancer cells inhibited the HCC recurrence in NAFLD. CONCLUSIONS ALOX12-12-HETE-GPR31 played an important role in HCC recurrence and might be a potential therapeutic target to reduce HCC recurrence after surgery in fatty livers.

中文翻译：

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缺血再灌注损伤通过ALOX12-12HETE-GPR31信号轴促进脂肪肝中肝细胞癌的复发。

背景技术已经显示缺血再灌注损伤（IRI）增加了肝脏手术后肿瘤复发的风险。同样，非酒精性脂肪肝疾病（NAFLD）与HCC复发增加相关。ALOX12-12-HETE途径在肝脏IRI和NASH中均被激活。同样，ALOX12-12-HETE已显示出介导肿瘤发生和进展的能力。因此，我们的研究旨在调查ALOX12-12-HETE-GPR31途径是否参与IRI诱导的NAFLD肝癌复发。方法使用HCC小鼠模型模拟NAFLD中的HCC复发。进行了Western Blot，qPCR，Elisa和免疫荧光分析，以评估HCC复发期间多种信号通路的变化，包括ALOX12-12-HETE轴，EMT，MMP和PI3K / AKT /NF-κB信号通路。我们还通过siRNA测量了GPR31的表达和功能变化。结果ALOX12-12-HETE通路在肝脏IRI中被激活，在NAFLD中其激活进一步增强，与正常肝脏相比，脂肪肝中HCC的复发更为严重。ML355抑制ALOX12-12-HETE可减少脂肪肝中HCC的复发。体外研究表明12-HETE通过激活PI3K / AKT /NF-κB途径增加GPR31的表达并诱导上皮-间质转化（EMT）和基质金属蛋白（MMPs）。此外，癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。结果ALOX12-12-HETE通路在肝脏IRI中被激活，在NAFLD中其激活进一步增强，与正常肝脏相比，脂肪肝中HCC的复发更为严重。ML355抑制ALOX12-12-HETE可减少脂肪肝中HCC的复发。体外研究表明12-HETE通过激活PI3K / AKT /NF-κB途径增加GPR31的表达并诱导上皮-间质转化（EMT）和基质金属蛋白（MMPs）。此外，癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。结果ALOX12-12-HETE通路在肝脏IRI中被激活，在NAFLD中其激活进一步增强，与正常肝脏相比，脂肪肝中HCC的复发更为严重。ML355抑制ALOX12-12-HETE可减少脂肪肝中HCC的复发。体外研究表明12-HETE通过激活PI3K / AKT /NF-κB途径增加GPR31的表达并诱导上皮-间质转化（EMT）和基质金属蛋白（MMPs）。此外，癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。ML355抑制ALOX12-12-HETE可减少脂肪肝中HCC的复发。体外研究表明12-HETE通过激活PI3K / AKT /NF-κB途径增加GPR31的表达并诱导上皮-间质转化（EMT）和基质金属蛋白（MMPs）。此外，癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。ML355抑制ALOX12-12-HETE可减少脂肪肝中HCC的复发。体外研究表明12-HETE通过激活PI3K / AKT /NF-κB途径增加GPR31的表达并诱导上皮-间质转化（EMT）和基质金属蛋白（MMP）。此外，癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。癌细胞中GPR31的敲低抑制了NAFLD中HCC的复发。结论ALOX12-12-HETE-GPR31在HCC复发中起重要作用，并且可能是降低脂肪肝手术后HCC复发的潜在治疗靶点。