SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans.
SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans.
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SLC26A9 缺陷导致小鼠胃上皮内瘤变和人类侵袭性胃癌
DOI：
10.1007/s13402-022-00672-x
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发表时间：
2022-06
影响因子：
6.6
通讯作者：
Tuo, Biguang
中科院分区：
文献类型：
--
作者：
Liu, Xuemei;Li, Taolang;Ma, Zhiyuan;Riederer, Brigitte;Yuan, Dumin;Zhu, Jiaxing;Li, Yunhua;An, Jiaxing;Wen, Guorong;Jin, Hai;Yang, Xiao;Seidler, Ursula;Tuo, Biguang
溶质载体家族26成员（SLC26A9）是一种氯离子单向转运体，在胃黏膜中表达水平极高。在此，我们描述了slc26a9基因敲除小鼠以及壁细胞特异性敲除的slc26a9fl/fl/Atp4b - Cre小鼠胃黏膜的形态学和分子改变，并在一组胃癌（GC）患者中将SLC26A9的表达水平与形态学及临床参数进行关联分析。
通过免疫组织化学（IHC）、定量逆转录聚合酶链反应（qRT - PCR）、原位杂交及RNA微阵列分析，对与转运和酶功能、增殖、凋亡、炎症、屏障完整性、化生及肿瘤发生相关基因的表达模式展开研究。在原发性人类胃癌组织及胃癌细胞系中，对SLC26A9的表达以及细胞/临床表型进行研究。
我们发现，小鼠中Slc26a9基因的完全缺失和壁细胞选择性缺失，均会导致胃的癌前病变和恶性病变自发形成。在炎症环境中，观察到胃干细胞分化失调、Wnt信号通路激活、细胞过度增殖、凋亡受抑制以及化生现象。对人类胃的癌前和癌组织分析显示，从萎缩性胃炎到胃癌，SLC26A9的表达逐渐降低，且SLC26A9的下调与患者生存率相关。在胃癌细胞中外源表达SLC26A9，可诱导氯离子/碳酸氢根离子交换体AE2上调、细胞周期阻滞于G2/M期并诱导凋亡，同时抑制细胞的增殖、迁移和侵袭。
我们的数据表明，壁细胞中SLC26A9的缺失足以引发胃化生及肿瘤性病变的发生。此外，我们发现，在人类胃癌发生过程中SLC26A9表达降低，且在胃癌细胞中外源表达SLC26A9可降低其恶性行为。
网络版包含补充材料，网址为10.1007/s13402 - 022 - 00672 - x 。
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. 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. 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. 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. The online version contains supplementary material available at 10.1007/s13402-022-00672-x.
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