کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8455372 | 1548021 | 2014 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Decorin deficiency promotes hepatic carcinogenesis
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کلمات کلیدی
ECMAP4EGFRCyclin-dependent kinase inhibitor p21extracellular signal regulated kinase 1/2SLRPIGF-IRGSK3βPDGFRHepatocarcinogenesisCDK4DenRTKc-Myc - c-mycERK1/2 - ERK1 / 2HCC - HCCMAPK - MAPKp21WAF1/Cip1 - p21WAF1 / Cip1alpha fetoprotein - آلفا فتوپروتئینβ-catenin - بتا-کاتنینAFP - تست AFP یا آلفا فیتو پروتئینThioacetamide - تیوات آمیدCyclin Dependent Kinase 4 - سیکلین وابسته به کیناز 4Cell signaling - سیگنالینگ سلولیExtracellular matrix - ماتریکس خارج سلولیwild type - نوع وحشیdiethyl nitrosamine - نیتروزانای دی اتیلsmall leucine-rich proteoglycan - پروتئگلیکان غنی از لوسین استretinoblastoma protein - پروتئین رتینوبلاستوماmitogen activated protein kinase - پروتئین کیناز فعال Mitogen فعال استHepatocellular carcinoma - کارسینوم هپاتوسلولار(کارسینوم سلولهای استخوانی)Glutamine synthetase - گلوتامین سنتتازGlycogen synthase kinase 3β - گلیکوزین سنتاز کیناز 3βReceptor Tyrosine Kinase - گیرنده تیروزین کینازplatelet-derived growth factor receptor - گیرنده عامل فاکتور رشد یافته پلاکتEpidermal growth factor receptor - گیرنده فاکتور رشد اپیدرمال
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
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چکیده انگلیسی
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 Dcnâ/â 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Matrix Biology - Volume 35, April 2014, Pages 194-205
Journal: Matrix Biology - Volume 35, April 2014, Pages 194-205
نویسندگان
Zsolt Horváth, Ilona Kovalszky, Alexandra Fullár, Katalin Kiss, Zsuzsa Schaff, Renato V. Iozzo, Kornélia Baghy,