致癌性 KRas 抑制胰腺导管细胞炎症相关的衰老。
Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.
机构信息
Cell and Molecular Biology Program, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
出版信息
Cancer Cell. 2010 Nov 16;18(5):448-58. doi: 10.1016/j.ccr.2010.10.020.
Abstract
Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16(INK4A) induction. Moreover, the KRas-Twist-p16(INK4A) senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.
摘要
KRas 基因突变是胰腺导管腺癌（PDAC）中最早也是最常检测到的遗传病变。然而，致癌 KRas 在 PDAC 发病机制中的确切作用尚不完全清楚。在这里，我们报告致癌 KRas 的内源性表达抑制了原代胰腺导管上皮细胞（PDEC）的过早衰老。致癌 KRas 介导的衰老旁路是通过上调碱性螺旋-环-螺旋转录因子 Twist 来实现的，而 Twist 反过来又阻止了 p16(INK4A)的诱导。此外，KRas-Twist-p16(INK4A)衰老旁路途径在体内被用于防止胰腺导管上皮的炎症相关衰老。我们的研究结果表明，致癌 KRas 通过防止细胞进入永久生长停滞状态，可能有助于 PDAC 的发生。
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本文引用的文献
1
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Cancer Cell. 2010 Aug 9;18(2):135-46. doi: 10.1016/j.ccr.2010.06.013.
2
The senescence-associated secretory phenotype: the dark side of tumor suppression.衰老相关的分泌表型：肿瘤抑制的阴暗面。
Annu Rev Pathol. 2010;5:99-118. doi: 10.1146/annurev-pathol-121808-102144.
3
Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice.β-连环蛋白阻断 Kras 依赖性的小鼠腺泡重编程为胰腺癌前病变。
J Clin Invest. 2010 Feb;120(2):508-20. doi: 10.1172/JCI40045. Epub 2010 Jan 11.
4
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5
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6
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Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19035-9. doi: 10.1073/pnas.0910009106. Epub 2009 Oct 26.
7
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9
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10
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