Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, No.180 Fenglin Rd., Xuhui District, Shanghai 200032, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, No.180 Fenglin Rd., Xuhui District, Shanghai 200032, China.
Exp Cell Res. 2018 Sep 15;370(2):468-477. doi: 10.1016/j.yexcr.2018.07.011. Epub 2018 Jul 7.
The aim of this study was to investigate whether treatment-damaged hepatocellular carcinoma (HCC) would accelerate liver cirrhosis through promoting the activities of hepatic stellate cells (HSCs). HCC cells were exposed to chemotherapeutic agent or hypoxia to mimic the transarterial chemoembolization (TACE)-like treatment. Growth differentiation factor 15 (GDF15) expression was increased in cisplatin- or hypoxia-treated HCC cells. Treatment-induced GDF15 increase in HCC cells was mediated by p38MAPK, JNK, ERK1/2 activation. GDF15 from treatment-damaged HCC cells enhanced the proliferation and collagen synthesis of HSCs through ERK1/2- and Smad3-dependent pathways. Metformin significantly reduced the GDF15 production from treatment-damaged HCC cells by targeting JNK. The use of metformin could attenuate the in vivo fibrotic activities of HSCs promoted by treatment-damaged HCC cells and inhibit GDF15 expression. In conclusion, treatment-damaged HCC accelerates fibrosis by promoting the activities of HSCs via GDF15 secretion, which could be reversed by metformin. This provides a potential therapeutic target for alleviating TACE-aggravated liver cirrhosis.
本研究旨在探讨治疗损伤的肝细胞癌（HCC）是否通过促进肝星状细胞（HSCs）的活性加速肝硬化。用化疗药物或缺氧处理 HCC 细胞以模拟经动脉化疗栓塞（TACE）样治疗。顺铂或缺氧处理的 HCC 细胞中生长分化因子 15（GDF15）表达增加。HCC 细胞中治疗诱导的 GDF15 增加是由 p38MAPK、JNK、ERK1/2 激活介导的。来自治疗损伤的 HCC 细胞的 GDF15 通过 ERK1/2 和 Smad3 依赖性途径增强 HSCs 的增殖和胶原合成。二甲双胍通过靶向 JNK 显著减少治疗损伤的 HCC 细胞中 GDF15 的产生。二甲双胍的使用可以通过抑制 GDF15 的表达来减弱治疗损伤的 HCC 细胞促进的 HSCs 的体内纤维化活性。总之，治疗损伤的 HCC 通过 GDF15 分泌促进 HSCs 的活性来加速纤维化，这可以通过二甲双胍逆转。这为缓解 TACE 加重的肝硬化提供了一个潜在的治疗靶点。
