Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU-Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Department of Gastroenterology and Hepatology, Clinic of Medicine, St Olav's University Hospital, 7491 Trondheim, Norway.
Int J Mol Sci. 2020 Jan 31;21(3):927. doi: 10.3390/ijms21030927.
Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H/KATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.
质子泵抑制剂的使用与胃癌风险增加相关，这可能是通过高胃泌素血症介导的。痉挛多肽表达化生（SPEM）已被提议作为胃癌的前体。我们研究了胃泌素受体拮抗剂 netazepide（NTZ）或载体对 H/KATPase β亚单位敲除（KO）和野生型（WT）小鼠胃体黏膜的影响。通过组织病理学、免疫组织化学（IHC）、原位杂交（ISH）和全基因组基因表达分析评估胃体，重点关注 SPEM 和神经内分泌（NE）细胞的标志物。KO 小鼠胃体有明显的肥大、黏膜内和黏膜下囊肿以及广泛的 SPEM 和 NE 细胞标志物表达，但在胃窦中没有。与 WT 小鼠相比，KO 小鼠中有许多与 SPEM 相关的基因上调。NTZ 减少了肥大、囊肿、炎症和 NE 增生。然而，NTZ 既不影响 SPEM 标志物的表达，也不影响与 SPEM 相关的基因的表达。总之，NTZ 可预防黏膜肥大、囊肿形成和 NE 细胞增生，但不影响 SPEM。在这种动物模型中，SPEM 的存在似乎与高胃泌素血症引起的变化无关。
