De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis.
De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis.
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DOI：
10.1038/sj.bjc.6603782
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发表时间：
2007-06-18
影响因子：
8.8
通讯作者：
Watson, S A
中科院分区：
文献类型：
--
作者：
El-Zaatari, M;Tobias, A;Grabowska, A M;Kumari, R;Scotting, P J;Kaye, P;Atherton, J;Clarke, P A;Powe, D G;Watson, S A
本研究调查了胰岛素-胃泌素（InsGas）高胃泌素血症小鼠+/−猫螺杆菌（H.猫）感染。与正常粘膜相比，Sonic hedgehog基因和蛋白质表达在来自未感染小鼠的化生前病变中减少（90%基因减少，P<0.01）。Sonic hedgehog在H.与化生前病变相比，猫感染的小鼠（3.5倍增加，P<0.01）。此外，Shh靶基因，胶质瘤相关癌基因（Gli）-1，在InsGas小鼠的胃腺中显著减少（减少75%，P<0.05），并在H.猫感染（P<0.05，腺体基部，P<0.01，化生腺体间质）。H.通过测量靶细胞因子白细胞介素-8（IL-8）对AGS和MGLVA 1细胞中Shh表达的影响来研究猫激活Shh通路，所述靶细胞因子白细胞介素-8（IL-8）显示在生理浓度下诱导Shh表达。H.猫体内炎性浸润组织中NF-κB的表达，以及炎性浸润组织和化生性病变中IL-8小鼠同源物蛋白KC的表达。Sonic hedgehog通路的再激活与化生性病变增殖的增加相一致（感染与未感染小鼠分别为15.75%与4.39%，P<0.001）。此外，Shh过表达增加了胃癌细胞系AGS的生长速率。抗凋亡蛋白bcl-2在感染小鼠的间质中表达，沿着第二个Shh靶基因patched-1（P=0.0001，化生腺间质）。这项研究提供的证据表明，重新激活的Shh信号从化生前到晚期化生病变的胃，并概述了重要性的Shh通路作为一个潜在的化学预防胃癌发生的目标。
This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/− Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-κB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.