背景:溶质载体家族26成员(SLC26A9)是一种在胃粘膜中具有非常高表达水平的Cl-单转体。这里,我们描述了slc26a9-/-小鼠和选择性壁细胞缺失的slc26a9fl/fl/Atp4b-Cre小鼠胃粘膜的形态学和分子改变,并将一组胃癌(GC)患者的SLC26A9表达水平与形态学和临床参数相关联.
方法:与转运和酶功能相关的基因的表达模式,扩散,凋亡,炎症,屏障完整性,通过免疫组织化学(IHC)研究了上皮化生和瘤形成的发展,定量RT-PCR,原位杂交和RNA微阵列分析。在原代人GC组织和GC细胞系中研究了SLC26A9表达和细胞/临床表型。
结果:我们发现小鼠中完全和壁细胞选择性Slc26a9缺失均导致胃癌前和恶性病变的自发发展。炎症环境中胃干细胞分化失调,激活的Wnt信号,细胞过度增殖,观察到细胞凋亡抑制和化生。人胃癌前组织和癌组织的分析显示,SLC26A9表达从萎缩性胃炎到GC逐渐降低,SLC26A9的下调与患者生存率相关。在GC细胞中外源性表达SLC26A9可诱导Cl-/HCO3-交换子AE2,G2/M细胞周期阻滞和凋亡的上调,并抑制其增殖,移民和入侵。
结论:我们的数据表明壁细胞中SLC26A9缺失足以引发胃上皮化生和肿瘤病变的发展。此外,我们发现SLC26A9在人胃癌发生过程中表达降低,外源性SLC26A9在GC细胞中的表达降低了其恶性行为。
BACKGROUND: Solute carrier family 26 member (
SLC26A9) is a Cl- uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of
slc26a9-/- mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate
SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients.
METHODS: The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines.
RESULTS: We found that both complete and parietal cell-selective
Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl-/HCO3- exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion.
CONCLUSIONS: Our data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous
SLC26A9 expression in GC cells reduces their malignant behavior.