Periostin deficiency reduces diethylnitrosamine-induced liver cancer in mice by decreasing hepatic stellate cell activation and cancer cell proliferation
Periostin deficiency reduces diethylnitrosamine-induced liver cancer in mice by decreasing hepatic stellate cell activation and cancer cell proliferation
复制标题
骨膜素缺乏通过减少肝星状细胞活化和癌细胞增殖来减少二乙基亚硝胺诱导的小鼠肝癌
DOI：
10.1002/path.5756
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发表时间：
2021-08-05
影响因子：
7.3
通讯作者：
Ouyang, Gaoliang
中科院分区：
文献类型：
--
作者：
Xiao, Hongjun;Zhang, Yezhen;Ouyang, Gaoliang
骨膜蛋白是肝脏疾病（如肝骨化病、非酒精性脂肪性肝炎、炎症和纤维化）发病机制中的关键细胞外调节因子。骨膜蛋白也参与肝细胞癌（HCC）的进展。然而，在HCC的发病机制中，骨膜素在肝星状细胞（HSC）活化和肿瘤细胞增殖中的分子机制仍不清楚。我们证明，在二乙基亚硝胺（DEN）诱导的小鼠HCC组织中，骨膜蛋白显著上调，敲除骨膜蛋白会损害DEN诱导的HCC的发展。骨膜蛋白主要来源于活化的HSC， HSC缺乏骨膜蛋白会损害HSC的活化，抑制HSC促进的肝癌细胞体外增殖和体内肿瘤生长。从机制上讲，骨膜素通过整合素- fak - stat3 -骨膜素途径促进HSC活化，并通过激活ERK增强HCC细胞增殖。在HCC临床标本中，骨膜素与HSC活化和细胞增殖呈正相关。总的来说，我们的研究结果表明，HSC衍生的骨膜蛋白通过自分泌的骨膜蛋白-整合素- fak - stat3 -骨膜蛋白回路增强HSC的激活，并通过旁分泌的ERK途径增强HCC细胞的增殖，从而促进HCC的发展。因此，在HCC的发展过程中，骨膜蛋白是一个多方面的细胞外调节因子。(c) 2021大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Periostin is a critical extracellular regulator in the pathogenesis of liver disorders such as hepatosteatosis, non-alcoholic steatohepatitis, inflammation, and fibrosis. Periostin is also involved in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms of periostin in hepatic stellate cell (HSC) activation and tumor cell proliferation in the pathogenesis of HCC remain largely unknown. We demonstrate that periostin is markedly upregulated in diethylnitrosamine (DEN)-induced mouse HCC tissues and that periostin knockout impairs DEN-induced HCC development. Periostin is predominantly derived from activated HSCs and periostin deficiency in HSCs impairs HSC activation and inhibits HSC-promoted HCC cell proliferation in vitro and tumor growth in vivo. Mechanistically, periostin promotes HSC activation through the integrin-FAK-STAT3-periostin pathway and augments HCC cell proliferation by activating ERK. There are positive correlations between periostin and HSC activation and cell proliferation in HCC clinical samples. Collectively, our findings demonstrate that HSC-derived periostin promotes HCC development by enhancing HSC activation through an autocrine periostin-integrin-FAK-STAT3-periostin circuit and by augmenting HCC cell proliferation via the ERK pathway in a paracrine manner. Thus, periostin is a multifaceted extracellular regulator in the development of HCC. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.