Gastric adenocarcinoma cells secrete sulfomucins, but their role in gastric tumorigenesis remains unclear. To address that question, we generated A4gnt/Chst4 double-knockout (DKO) mice by crossing A4gnt knockout (KO) mice, which spontaneously develop gastric adenocarcinoma, with Chst4 KO mice, which are deficient in the sulfotransferase GlcNAc6ST-2. A4gnt/Chst4 DKO mice lack gastric sulfomucins but developed gastric adenocarcinoma. Unexpectedly, severe gastric erosion occurred in A4gnt/Chst4 DKO mice at as early as 3 weeks of age, and with aging these lesions were accompanied by gastritis cystica profunda (GCP). Cxcl1, Cxcl5, Ccl2, and Cxcr2 transcripts in gastric mucosa of 5-week-old A4gnt/Chst4 DKO mice exhibiting both hyperplasia and severe erosion were significantly upregulated relative to age-matched A4gnt KO mice, which showed hyperplasia alone. However, upregulation of these genes disappeared in 50-week-old A4gnt/Chst4 DKO mice exhibiting high-grade dysplasia/adenocarcinoma and GCP. Moreover, Cxcl1 and Cxcr2 were downregulated in A4gnt/Chst4 DKO mice relative to age-matched A4gnt KO mice exhibiting adenocarcinoma alone. These combined results indicate that the presence of sulfomucins prevents severe gastric erosion followed by GCP in A4gnt KO mice by transiently regulating a set of inflammation-related genes, Cxcl1, Cxcl5, Ccl2, and Cxcr2 at 5 weeks of age, although sulfomucins were not directly associated with gastric cancer development.

中文翻译：

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对 A4gnt 敲除小鼠的分析揭示了胃磺粘蛋白在预防深部囊性胃炎中的重要作用。


胃腺癌细胞分泌磺粘蛋白，但其在胃肿瘤发生中的作用仍不清楚。为了解决这个问题，我们通过将自发发生胃腺癌的 A4gnt 敲除 (KO) 小鼠与缺乏磺基转移酶 GlcNAc6ST-2 的 Chst4 KO 小鼠杂交，产生了 A4gnt/Chst4 双敲除 (DKO) 小鼠。 A4gnt/Chst4 DKO 小鼠缺乏胃磺粘蛋白，但发生胃腺癌。出乎意料的是，A4gnt/Chst4 DKO 小鼠早在 3 周龄时就出现了严重的胃糜烂，并且随着年龄的增长，这些病变还伴有深部囊性胃炎 (GCP)。 5 周龄 A4gnt/Chst4 DKO 小鼠胃粘膜中的 Cxcl1、Cxcl5、Ccl2 和 Cxcr2 转录本表现出增生和严重糜烂，相对于年龄匹配的 A4gnt KO 小鼠（仅表现出增生）显着上调。然而，这些基因的上调在 50 周龄的 A4gnt/Chst4 DKO 小鼠中消失，表现出高度不典型增生/腺癌和 GCP。此外，相对于仅表现出腺癌的年龄匹配的 A4gnt KO 小鼠，A4gnt/Chst4 DKO 小鼠中的 Cxcl1 和 Cxcr2 下调。这些综合结果表明，磺粘蛋白的存在通过在 5 周龄时短暂调节一组炎症相关基因 Cxcl1、Cxcl5、Ccl2 和 Cxcr2 来防止 A4gnt KO 小鼠中严重的胃糜烂，随后发生 GCP，尽管磺粘蛋白并不直接作用于 A4gnt KO 小鼠。与胃癌的发生发展有关。