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首页> 外文期刊>The journal of clinical investigation >CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice
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CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

机译：CD98表达调节小鼠的肠道稳态，炎症和结肠炎相关癌症

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Expression of the transmembrane glycoprotein CD98 (encoded by SLC3A2 ) is increased in intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), and in various carcinomas, yet its pathogenetic role remains unknown. By generating gain- and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer.
机译：跨膜糖蛋白CD98（由SLC3A2编码）的表达在肠炎性疾病（例如炎性肠病（IBD））和各种癌症中增加，但其致病作用仍然未知。通过生成具有基因操纵的CD98表达的功能增强和丧失功能的小鼠模型，特别是在肠道上皮细胞（IEC）中，我们探索了CD98在肠道稳态，炎症和结肠炎相关的肿瘤发生中的作用。 IEC特异性CD98过表达诱导肠道稳态缺陷，并增加对DSS诱导的结肠炎的炎症反应，从而促进小鼠结肠炎相关的肿瘤发生。进一步的分析表明，IEC特异性CD98过表达诱导肿瘤发生的能力与其诱导屏障功能障碍，刺激细胞增殖和促炎性介质产生的能力有关。为了验证这些结果，我们构建了携带条件性Slc3a2等位基因的小鼠，并将其与Villin-Cre小鼠杂交，使得CD98仅在IEC中被下调。这些小鼠表现出减弱的炎性反应和对DSS诱导的结肠炎和与结肠炎相关的肿瘤发生的抵抗力。总之，我们的数据表明，肠道CD98表达在控制肠道稳态和先天免疫反应中起着至关重要的作用。因此，IEC中CD98表达的调节代表了一种有希望的治疗策略，用于治疗和预防炎症性肠病，例如IBD和结肠炎相关的癌症。

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