The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling
The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling
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DOI：
10.1016/j.jss.2013.12.010
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发表时间：
2014-04-01
影响因子：
2.2
通讯作者：
Sicklick, Jason K.
中科院分区：
文献类型：
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作者：
Magistri, Paolo;Leonard, Stephanie Y.;Sicklick, Jason K.
背景资料：肝细胞癌（HCC）通常代表两种疾病，因为它经常出现在肝星状细胞（HSC）增殖和活化引起的肝硬化背景下。以前，我们确定Hedgehog（Hh）信号调节HSC活力和纤维蛋白生成，以及HCC肿瘤发生。虽然越来越多的人认识到HSC和HCC通过旁分泌信号传导进行交流，但Hh在这一过程中的作用才刚刚出现。我们假设，一个分泌的肝癌肿瘤标志物和Hh介质，磷脂酰肌醇蛋白聚糖3（GPC 3），可能会调节HSC.Methods：使用三个人肝癌细胞系（Hep 3B，PLC/PRF/5和SK-Hep-1）和一个Hhresponsive人HSC系（LX-2），我们开发了两个在体外模型的肝癌-HSC旁分泌信号使用Transwell共培养系统和肝癌条件培养基。然后，我们评估了这些模型的影响，以及GPC 3，对HSC的活力和基因expression.Results：使用我们的共培养和条件培养基模型，我们证明了三个肝癌细胞系降低HSC的活力。此外，我们证明了重组GPC 3剂量依赖性地降低LX-2的活力，同时抑制调节HSC活力的Hh靶基因的表达。最后，GPC 3的抑制作用，细胞活力和Hh靶基因表达的部分废除肝素，竞争对手GPC 3 binding.Conclusions：第一次，我们表明，GPC 3，肝癌的生物标志物和Hh调解人，调节人HSC活力通过调节Hh信号。这扩展了现有的数据，表明肝脏中肿瘤间质相互作用的作用，并表明GPC 3在这一过程中发挥作用。(c)2014爱思唯尔公司All rights reserved.
Background: Hepatocellular carcinoma (HCC) frequently represents two diseases as it often arises in the setting of cirrhosis caused by the proliferation and activation of hepatic stellate cells (HSCs). Previously, we identified that Hedgehog (Hh) signaling regulates HSC viability and fibrinogenesis, as well as HCC tumorigenesis. Although it is increasingly recognized that HSCs and HCCs communicate via paracrine signaling, Hh's role in this process is just emerging. We hypothesized that a secreted HCC tumor marker and Hh mediator, glypican 3 (GPC3), may regulate HSC.Methods: Using three human HCC lines (Hep3B, PLC/PRF/5 and SK-Hep-1) and one Hhresponsive human HSC line (LX-2), we developed two in vitro models of HCC-to-HSC paracrine signaling using a Transwell coculture system and HCC-conditioned media. We then evaluated the effects of these models, as well as GPC3, on HSC viability and gene expression.Results: Using our coculture and conditioned media models, we demonstrate that the three HCC lines decrease HSC viability. Furthermore, we demonstrate that recombinant GPC3 dose-dependently decreases the LX-2 viability while inhibiting the expression of Hh target genes that regulate HSC viability. Finally, GPC3's inhibitory effects on cell viability and Hh target gene expression are partially abrogated by heparin, a competitor for GPC3 binding.Conclusions: For the first time, we show that GPC3, an HCC biomarker and Hh mediator, regulates human HSC viability by regulating Hh signaling. This expands on existing data suggesting a role for tumorestroma interactions in the liver and suggests that GPC3 plays a role in this process. (c) 2014 Elsevier Inc. All rights reserved.