Suppression of galectin-4 attenuates peritoneal metastasis of poorly differentiated gastric cancer cells
Suppression of galectin-4 attenuates peritoneal metastasis of poorly differentiated gastric cancer cells
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DOI：
10.1007/s10120-023-01366-5
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发表时间：
2023-01-25
期刊：
影响因子：
7.4
通讯作者：
Minamoto, Toshinari
中科院分区：
文献类型：
--
作者：
Ideo, Hiroko;Tsuchida, Akiko;Minamoto, Toshinari
背景腹膜播散最常见于转移性和/或复发性胃癌，是一种无法手术且缺乏有效治疗的疾病。分子靶向药物的使用也受到限制；因此，迫切需要确定新的治疗靶点并提高我们对这种转移性癌症的了解。在这项研究中，我们关注的是半乳糖凝集素4，它在具有高腹膜传播潜力的低分化细胞中特异性表达。方法我们使用CRISPR/Cas9介导的基因组编辑敲除NUGC4细胞中的半乳糖凝集素-4基因。将敲除细胞的增殖和腹膜癌形成与野生型和半乳糖凝集素 4 重新表达细胞进行比较。进行蛋白质印迹和邻近连接测定来鉴定受半乳糖凝集素4表达影响的相关分子。使用特定的 siRNA 研究了半乳糖凝集素 4 敲低对细胞增殖和腹膜转移的影响。采用免疫组织化学方法检测10例胃癌腹膜转移瘤中galectin-4的表达。结果抑制galectin-4的表达可减少胃癌恶性细胞的增殖和腹膜转移。 Galectin-4 敲除和敲低降低了活化的 c-MET 和 CD44 的表达。研究发现 Galectin-4 通过其碳水化合物结合能力与细胞表面的多种蛋白质相互作用，包括 CD44 和 c-MET。免疫组织化学显示所有检查患者的腹膜转移肿瘤细胞中均表达半乳糖凝集素4。结论我们阐明了半乳糖凝集素4在低分化胃癌细胞腹膜播散发展中的作用。我们的数据强调了半乳糖凝集素 4 在胃癌腹膜传播中的诊断和治疗潜力。
BackgroundPeritoneal dissemination, most often seen in metastatic and/or recurrent gastric cancer, is an inoperable condition that lacks effective treatment. The use of molecular targeted drugs is also limited; therefore, identifying novel therapeutic targets and improving our understanding of this metastatic cancer are an urgent requirement. In this study, we focused on galectin-4, which is specifically expressed in poorly differentiated cells with high potential for peritoneal dissemination.MethodsWe knocked out the galectin-4 gene in NUGC4 cells using CRISPR/Cas9-mediated genome editing. Proliferation and peritoneal cancer formation in knockout cells were compared with those in wild-type and galectin-4 re-expressing cells. Western blotting and proximity ligation assays were performed to identify associated molecules affected by the expression of galectin-4. The effect of galectin-4 knockdown on cell proliferation and peritoneal metastasis was studied using a specific siRNA. Expression of galectin-4 in peritoneal metastatic tumors from 10 patients with gastric cancer was examined by immunohistochemistry.ResultsSuppression of galectin-4 expression reduced proliferation and peritoneal metastasis of malignant gastric cancer cells. Galectin-4 knockout and knockdown reduced the expression of activated c-MET and CD44. Galectin-4 was found to interact with several proteins on the cell surface, including CD44 and c-MET, via its carbohydrate-binding ability. Immunohistochemistry showed galectin-4 expression in peritoneal metastatic tumor cells in all patients examined.ConclusionsWe clarified the role of galectin-4 in the development of peritoneal dissemination of poorly differentiated gastric cancer cells. Our data highlight the diagnostic and therapeutic potential of galectin-4 in the peritoneal dissemination of gastric cancer.