Lv Xing, Fang Cheng, Yin Ruozhe, Qiao Bowei, Shang Runze, Wang Jianlin, Song Wenjie, He Yong, Chen Yong
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P.R. China.
Oncotarget. 2017 Oct 31;8(62):105340-105355. doi: 10.18632/oncotarget.22186. eCollection 2017 Dec 1.
Evaluating the process and mechanism of fibrogenesis is essential in hepatocellular carcinoma (HCC), especially in hepatocyte transformation and oncogenic signaling. We evaluated the oncogenic role of agrin secreted by platelet-derived growth factor (PDGF)-induced hepatic stellate cell (HSC) in HCC. Cells were co-cultured to investigate the effect of activated HSC on hepatocytes. Liquid chromatography and protein profiling analysis were used to search the distinct proteins secreted in HSC supernatant. Sprague Dawley rats with Diethylnitrosamine (DEN)-induced HCC were used to simulate human liver cancer and sorafenib was administered to investigate its effect on hepatocarcinogenesis. A paired "two-tailed" Student -test and chi-square tests was used for statistical analysis. PDGF acted as an activator of the HSC and sorafenib inhibits the activation by blocking the combination of PDGF and PDGF receptor. The supernatant of activated HSCs promoted the proliferation, metastasis, and invasion of HL-7702 and SMMC-7721, as well as epithelial-mesenchymal transition (EMT). Agrin found in the HSC supernatant showed the same effect on SMMC-7721 as to the supernatant of activated LX-2. Furthermore, downregulation of agrin by siRNA could decrease the proliferation, metastasis, and invasion of SMMC-7721, and promote MET. Sorafenib prevented DEN-induced hepatocarcinogenesis and could alleviate the liver inflammation and fibrosis. Sorafenib could improve the liver function of Sprague Dawley rats by decreasing the serum levels of ALT and AST. These results demonstrate thatPDGF is an effective activator of HSC and sorafenib could inhibit the activation. experiment suggested sorafenib could alleviate the hepatocarcinogenesis mediated through agrin secretion and could be potential candidate for treatment of cirrhosis.
评估肝纤维化形成的过程和机制在肝细胞癌（HCC）中至关重要，尤其是在肝细胞转化和致癌信号传导方面。我们评估了血小板衍生生长因子（PDGF）诱导的肝星状细胞（HSC）分泌的聚集蛋白聚糖在HCC中的致癌作用。将细胞共培养以研究活化的HSC对肝细胞的影响。采用液相色谱和蛋白质谱分析来寻找HSC上清液中分泌的独特蛋白质。用二乙基亚硝胺（DEN）诱导的HCC的Sprague Dawley大鼠来模拟人类肝癌，并给予索拉非尼以研究其对肝癌发生的影响。采用配对“双尾”学生t检验和卡方检验进行统计分析。PDGF作为HSC的激活剂，而索拉非尼通过阻断PDGF与PDGF受体的结合来抑制激活。活化的HSC的上清液促进了HL-7702和SMMC-7721的增殖、转移和侵袭，以及上皮-间质转化（EMT）。在HSC上清液中发现的聚集蛋白聚糖对SMMC-7721的作用与活化的LX-2的上清液相同。此外，通过siRNA下调聚集蛋白聚糖可降低SMMC-7721的增殖、转移和侵袭，并促进间质-上皮转化（MET）。索拉非尼可预防DEN诱导的肝癌发生，并可减轻肝脏炎症和纤维化。索拉非尼可通过降低血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平来改善Sprague Dawley大鼠的肝功能。这些结果表明，PDGF是HSC的有效激活剂，而索拉非尼可抑制其激活。实验表明，索拉非尼可减轻通过聚集蛋白聚糖分泌介导的肝癌发生，可能是治疗肝硬化的潜在候选药物。
