Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis
Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis
复制标题
DOI：
10.1002/ijc.25469
复制
发表时间：
2011-03-15
影响因子：
6.4
通讯作者：
Kanzler, Stephan
中科院分区：
文献类型：
--
作者：
Maass, Thorsten;Thieringer, Florian R.;Kanzler, Stephan
肝细胞癌（HCC）的遗传基础已经建立，主要的信号通路，如p53、wnt信号、转化生长因子- β (tgf - β)和Ras信号通路，已被确定对HCC的发展至关重要。最近，血小板衍生生长因子（PDGFs）家族已经转移到关注的中心。我们已经报道了PDGF-B转基因小鼠自发发生肝纤维化。由于HCC很少发生在健康肝脏中，但在肝硬化阶段急剧增加，而肝硬化阶段是肝纤维化的初步阶段，因此我们研究了这些小鼠化学诱导的肝癌发生。用二乙基亚硝胺和苯巴比妥治疗小鼠诱导肝癌。在6个月大时，分析这些动物的肿瘤发展情况。PDGF-B转基因小鼠不仅发育不良病变的发生明显增加，而且其向HCC的恶性转化也明显增加。此外，我们能够确定PDGF-B信号在肝癌发展的不同阶段的关键作用。在这里，我们表明肝纤维化的发展可能是通过PDGF-B上调tgf - β受体。此外，PDGF-B的过表达还导致β -连环蛋白以及血管内皮生长因子和血小板内皮细胞粘附分子-1 （PECAM-1/CD31）的表达增加，这些因素都在致癌过程中起着确定的作用。我们能够通过PDGF-B扩展对HCC发展中关键遗传调控因子的理解，并解码必要的下游信号。
A genetic basis of hepatocellular carcinoma (HCC) has been well-established and major signaling pathways, such as p53, Wnt-signaling, transforming growth factor-beta (TGF-beta) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet-derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF-B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF-B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF-B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF-beta receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of beta-catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF-B and decode essential downstream signals.