Decorin deficiency promotes hepatic carcinogenesis.
Decorin deficiency promotes hepatic carcinogenesis.
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DOI：
10.1016/j.matbio.2013.11.004
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发表时间：
2014-04
期刊：
影响因子：
6.9
通讯作者：
Baghy, Kornelia
中科院分区：
文献类型：
--
作者：
Horvath, Zsolt;Kovalszky, Ilona;Fullar, Alexandra;Kiss, Katalin;Schaff, Zsuzsa;Iozzo, Renato V.;Baghy, Kornelia
关键词：
肝细胞癌是世界上传播最快的癌症之一。在大多数情况下，炎症驱动的纤维化或肝硬化先于肿瘤的发展。在恶性转化过程中，肿瘤微环境经历质和量的变化，调节恶性细胞的行为。肝脏微环境的关键成分是富含亮氨酸的小蛋白聚糖核心蛋白聚糖，已知其主要通过阻断各种受体酪氨酸激酶 (RTK)，如 EGFR、Met、IGF-IR、PDGFR 和 VEGFR2 来干扰肿瘤发生的细胞事件。在这项研究中，我们在使用硫代乙酰胺或二乙基亚硝胺作为致癌物的两个肝癌发生实验模型中描述了核心蛋白聚糖缺乏引起的细胞信号传导事件。与野生型动物相比，核心蛋白聚糖的基因消除导致肿瘤发生率增加。这些发现与细胞周期蛋白依赖性激酶抑制剂 p21WAF1/CIP1 水平降低以及细胞周期蛋白依赖性激酶 4 引起的视网膜母细胞瘤蛋白磷酸化同时升高相关。稳态 p21Waf1/Cip1 水平降低与转录因子 AP4（一种已知的 p21Waf1/Cip1 转录抑制因子）表达增强以及 c-Myc 蛋白水平增强相关。此外，β-连环蛋白的易位是二乙基亚硝胺诱发的肿瘤中的典型事件。与此同时，在 Dcn−/− 肝脏中观察到 c-Myc 和 β-catenin 的磷酸化降低，这可能是由于 GSK3β 介导的这些蛋白质对蛋白酶体降解的靶向受到阻碍。我们发现，在缺乏核心蛋白聚糖的遗传背景中，四种 RTK 被组成型激活（磷酸化），包括核心蛋白聚糖的三个已知靶标，如 PDGFRα、EGFR、IGF-IR 和一种新型 RTK MSPR/RON。我们的研究结果为核心蛋白聚糖在肝癌发生过程中的关键体内作用提供了强有力的遗传证据，因为肝脏和肝基质中缺乏核心蛋白聚糖通过提供缺乏这种有效的泛 RTK 抑制剂的环境来促进实验性致癌。因此，我们的结果支持未来将核心蛋白聚糖用作肝癌的抗肿瘤剂。
Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21Waf1/Cip1 levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21Waf1/Cip1, and enhanced c-Myc protein levels. In addition, translocation of β-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and β-catenin was observed in Dcn−/− livers likely due to the hindered GSK3β-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRα, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates experimental carcinogenesis by providing an environment devoid of this potent pan-RTK inhibitor. Thus, our results support future utilization of decorin as an antitumor agent in liver cancer.
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影响因子：
3.5
作者：
Araki, Kentaro;Wakabayashi, Hiroki;Uchida, Atsumasa
通讯作者：
Uchida, Atsumasa
DOI：
10.1038/labinvest.2010.172
发表时间：
2011-03
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.9
作者：
Dunkman, Andrew A.;Buckley, Mark R.;Mienaltowski, Michael J.;Adams, Sheila M.;Thomas, Stephen J.;Satchell, Lauren;Kumar, Akash;Pathmanathan, Lydia;Beason, David P.;Iozzo, Renato V.;Birk, David E.;Soslowsky, Louis J.
通讯作者：
Soslowsky, Louis J.
DOI：
10.1074/jbc.m110.172841
发表时间：
2010-12-31
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Buraschi, Simone;Pal, Nutan;Iozzo, Renato V
通讯作者：
Iozzo, Renato V
影响因子：
4.7
作者：
Bi, Xiuli;Tong, Chang;Yang, Wancai
通讯作者：
Yang, Wancai