Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach.
Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach.
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DOI：
10.1053/j.gastro.2018.08.041
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发表时间：
2018-12
期刊：
影响因子：
29.4
通讯作者：
Fox JG
中科院分区：
文献类型：
--
作者：
Hagen SJ;Ang LH;Zheng Y;Karahan SN;Wu J;Wang YE;Caron TJ;Gad AP;Muthupalani S;Fox JG
claudin-18（CLDN 18）是一种跨膜紧密连接蛋白，其缺失是胃癌（GC）患者中与侵袭性表型和不良结局相关的早期事件。我们研究了CLDN 18损失是否也发生在GC的小鼠模型中，以及CLDN 18损失本身是否足以驱动GC的发展。在来自感染H.幽门螺杆菌6-15个月。使用B6：129 S5-CLDN 18 tm 1 Lex/Mmucd小鼠确定CLDN 18损失的后果，所述小鼠缺失胃中的CLDN 18基因和蛋白质表达。通过电子显微镜、组织病理学、超分辨率和常规共聚焦显微镜以及RNAseq分析组织。感染H. pylori感染后6个月显示CLDN 18损失，其随时间降低。CLDN 18具有基底外侧而不是顶端紧密连接定位，其首先从大多数胃腺中丢失，随后在颈部和表面细胞中破坏和衰减。CLDN 18缺陷型小鼠显示出增加的细胞增殖和与增殖性SPEM一致的分子特征，包括出生后7周的细胞信号传导缺陷。到20-30周，上皮内瘤变是浸润性粘膜下腺体的突出表型，到2年，出现大的局灶性发育不良息肉样肿瘤。H.小鼠中的幽门螺杆菌感染减弱了GC发展早期CLDN 18的表达，这与人类患者中的结果相似。CLDN 18的功能是调节小鼠胃中的细胞谱系分化和细胞信号传导，没有这些细胞谱系分化和细胞信号传导，肿瘤转化迅速发生。
Loss of claudin-18 (CLDN18), which is a membrane-spanning tight junction protein, is an early event associated with an aggressive phenotype and poor outcome in patients with gastric cancer (GC). We investigated whether CLDN18 loss also occurs in a mouse model of GC and whether CLDN18 loss, per se, is sufficient to drive GC development. Changes in CLDN18 expression were evaluated in archived tissues from B6:129 mice infected with H. pylori for 6–15 months. The consequence of CLDN18 loss was determined using B6:129S5-CLDN18tm1Lex/Mmucd mice, which delete CLDN18 gene and protein expression in stomach. Tissues were analyzed by electron microscopy, histopathology, super-resolution and conventional confocal microscopy, and RNAseq. Mice infected with H. pylori showed CLDN18 loss by 6 months post-infection that decreased over time. CLDN18, which had a basolateral rather than apical tight junction localization, was lost first from the majority of gastric glands followed by disruption and attenuation in neck and surface cells. CLDN18-deficient mice showed increased cellular proliferation and a molecular signature consistent with intestinalized proliferative SPEM that included defects in cellular signaling by 7 weeks after birth. By 20–30 weeks, intraepithelial neoplasia was the prominent phenotype with invasive submucosal glands and by 2-years, large and focally dysplastic polypoid tumors were present. H. pylori infection in mice attenuates the expression of CLDN18 early in GC development, which is similar to the results in human patients. CLDN18 functions to regulate cell lineage differentiation and cellular signaling in the mouse stomach, without which neoplastic transformation rapidly ensues.
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