کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3297922 | 1209891 | 2007 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Guanylyl Cyclase C Suppresses Intestinal Tumorigenesis by Restricting Proliferation and Maintaining Genomic Integrity
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کلمات کلیدی
AOMγ-H2AXAPCazoxymethaneGCCphosphorylated histone 2AXadenomatous polyposis coli - آدنوماتوز پولیپوزیس کولی یا آدنوماتوس پولیپوزیس کولای loss of heterozygosity - از دست دادن هتروزیگوتیسمheat-stable enterotoxin - انتروتوکسین گرم پایدارImmunohistochemistry - ایمونوهیستوشیمیIHC - ایمونوهیستوشیمیLOH - لوهانGuanylyl cyclase C - گوانلیول سیکلاز سی
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
Background & Aims: The most commonly lost gene products in colorectal carcinogenesis include guanylin and uroguanylin, endogenous ligands for guanylyl cyclase C (GCC). Beyond intestinal fluid balance, GCC mediates diarrhea induced by bacterial enterotoxins, and an inverse relationship exists between enterotoxigenic Escherichia coli infections producing the exogenous GCC ligand ST and colorectal cancer worldwide. However, the role of GCC in neoplasia remains obscure. Methods: Intestinal tumorigenesis was examined in wild-type (Gcc+/+) and GCC-deficient (Gccâ/â) mice carrying mutations in Apc (ApcMin/+) or exposed to the carcinogen azoxymethane. Markers of DNA damage, loss of Apc heterozygosity, and β-catenin mutations were used to assess genomic integrity. Hyperproliferation was explored using Ki67 and cell cycle markers. Apoptosis was quantified by transferase biotin-dUTP nick end labeling analysis. Results: In colons of ApcMin/+ mice, deletion of Gcc increased tumor incidence and multiplicity, reflecting uncoupling of loss of genomic integrity and compensatory apoptosis. Conversely, in the small intestine, elimination of Gcc increased tumorigenesis by enhancing proliferation without altering genomic integrity. Moreover, these distinct but mutually reinforcing mechanisms collaborate in azoxymethane-exposed mice, and deletion of Gcc increased tumor initiation and growth associated with hypermutation and hyperproliferation, respectively, in conjunction with attenuated apoptosis. Conclusions: GCC suppresses tumor initiation and growth by maintaining genomic integrity and restricting proliferation. This previously unrecognized role of GCC in inhibiting tumorigenesis, together with the invariant disruption in guanylin and uroguanylin expression early in carcinogenesis, and the uniform over-expression of GCC by tumors, underscores the potential of oral administration of GCC ligands for targeted prevention and therapy of colorectal cancer.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 133, Issue 2, August 2007, Pages 599-607
Journal: Gastroenterology - Volume 133, Issue 2, August 2007, Pages 599-607
نویسندگان
Peng Li, Stephanie Schulz, Alessandro Bombonati, Juan P. Palazzo, Terry M. Hyslop, Yihuan Xu, Amy A. Baran, Linda D. Siracusa, Giovanni M. Pitari, Scott A. Waldman,