Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
J Exp Clin Cancer Res. 2019 Dec 12;38(1):489. doi: 10.1186/s13046-019-1480-9.
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.
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.
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.
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.
缺血再灌注损伤（IRI）已被证明会增加肝手术后肿瘤复发的风险。此外，非酒精性脂肪性肝病（NAFLD）与 HCC 复发率增加有关。ALOX12-12-HETE 通路在肝 IRI 和 NASH 中均被激活。此外，已经表明 ALOX12-12-HETE 介导了肿瘤的发生和进展。因此，我们的研究旨在探讨 ALOX12-12-HETE-GPR31 通路是否参与了非酒精性脂肪性肝病（NAFLD）中 IRI 诱导的 HCC 复发。
使用 HCC 小鼠模型模拟 NAFLD 中的 HCC 复发。通过 Western Blot、qPCR、Elisa 和免疫荧光分析来评估 HCC 复发过程中多个信号通路的变化，包括 ALOX12-12-HETE 轴、上皮间质转化（EMT）、基质金属蛋白酶（MMPs）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。
ALOX12-12-HETE 通路在肝 IRI 中被激活，其在 NAFLD 中的激活进一步增强，导致脂肪性肝脏中的 HCC 复发比正常肝脏更为严重。通过 ML355 抑制 ALOX12-12-HETE 可减少脂肪性肝脏中的 HCC 复发。体外研究表明，12-HETE 通过激活 PI3K/AKT/NF-κB 通路增加 GPR31 的表达并诱导上皮间质转化（EMT）和基质金属蛋白酶（MMPs）。此外，在癌细胞中敲低 GPR31 可抑制 NAFLD 中的 HCC 复发。
ALOX12-12-HETE-GPR31 在 HCC 复发中起重要作用，可能是减少脂肪性肝脏手术后 HCC 复发的潜在治疗靶点。
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