{"title":"幽门螺杆菌诱发胃肿瘤发生过程中的整合素连接激酶：调控与预防潜力","authors":"Boqing Li, Jing He, Ruiqing Zhang, Sisi Liu, Xiaolin Zhang, Zhiqin Li, Chunlei Ma, Wenke Wang, Yingzi Cui, Ying Zhang","doi":"10.1111/hel.13109","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Integrin-linked kinase (ILK) is crucial in solid tumors by regulating the Hippo-Yes-associated protein 1 (YAP) pathway. This study aimed to uncover how <i>Helicobacter pylori</i> influences ILK levels and its role in regulating YAP during <i>H. pylori</i>-induced gastric cancer.</p>\n </section>\n \n <section>\n \n <h3> Materials and Methods</h3>\n \n <p>GES-1 cells with stable <i>Ilk</i> knockdown and overexpression and a mouse carcinogenesis model for <i>H. pylori</i> infection were constructed. And ILK, the phosphorylated mammalian STE20-like protein kinase 1 (MST1), large tumor suppressor 1 (LATS1; S909, T1079), and YAP (S109, S127) were detected in cells, and mice by western blotting, as well as fluorescence intensity of YAP were assayed by immunofluorescence. YAP downstream genes <i>Igfbp4</i> and <i>Ctgf</i>, the pathological changes and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β), and nitric oxide (NO) levels in mice gastric tissues were detected by real-time PCR, H&E, and ELISA assays.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>In this study, stable <i>Ilk</i> knockdown cells exhibited significantly higher phosphorylated levels of MST1, LATS1, and YAP, as well as increased YAP in the nuclei of GES-1 cells. Conversely, cells with <i>Ilk</i> overexpression showed opposite results. <i>H. pylori</i> infection led to decreased ILK levels in gastric epithelial cells but increased ILK levels in gastric cancer cell lines (MGC803, SGC7901) and gastric cancer tissues in mice. Treatment with the ILK inhibitor OST-T315 elevated the phosphorylated MST, LATS1, and YAP levels, and inhibited the mRNA levels of <i>Igfbp4</i> and <i>Ctgf</i> at 44, 48 week-aged mice. OST-T315 also reduced the release of TNF-α, IL-6, IL-1β, and NO, as well as the progression of gastric cancer caused by <i>H. pylori</i> and <i>N</i>-Nitroso-<i>N</i>-methylurea (NMU) treatment.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Upon initiation of gastric tumorigenesis signals, <i>H. pylori</i> increases ILK levels and suppresses Hippo signaling, thereby promoting YAP activation and gastric cancer progression. ILK can serve as a potential prevention target to impede <i>H. pylori</i>-induced gastric cancer.</p>\n </section>\n </div>","PeriodicalId":13223,"journal":{"name":"Helicobacter","volume":"29 4","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integrin-Linked Kinase in the Development of Gastric Tumors Induced by Helicobacter pylori: Regulation and Prevention Potential\",\"authors\":\"Boqing Li, Jing He, Ruiqing Zhang, Sisi Liu, Xiaolin Zhang, Zhiqin Li, Chunlei Ma, Wenke Wang, Yingzi Cui, Ying Zhang\",\"doi\":\"10.1111/hel.13109\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Integrin-linked kinase (ILK) is crucial in solid tumors by regulating the Hippo-Yes-associated protein 1 (YAP) pathway. This study aimed to uncover how <i>Helicobacter pylori</i> influences ILK levels and its role in regulating YAP during <i>H. pylori</i>-induced gastric cancer.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Materials and Methods</h3>\\n \\n <p>GES-1 cells with stable <i>Ilk</i> knockdown and overexpression and a mouse carcinogenesis model for <i>H. pylori</i> infection were constructed. And ILK, the phosphorylated mammalian STE20-like protein kinase 1 (MST1), large tumor suppressor 1 (LATS1; S909, T1079), and YAP (S109, S127) were detected in cells, and mice by western blotting, as well as fluorescence intensity of YAP were assayed by immunofluorescence. YAP downstream genes <i>Igfbp4</i> and <i>Ctgf</i>, the pathological changes and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β), and nitric oxide (NO) levels in mice gastric tissues were detected by real-time PCR, H&E, and ELISA assays.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>In this study, stable <i>Ilk</i> knockdown cells exhibited significantly higher phosphorylated levels of MST1, LATS1, and YAP, as well as increased YAP in the nuclei of GES-1 cells. Conversely, cells with <i>Ilk</i> overexpression showed opposite results. <i>H. pylori</i> infection led to decreased ILK levels in gastric epithelial cells but increased ILK levels in gastric cancer cell lines (MGC803, SGC7901) and gastric cancer tissues in mice. Treatment with the ILK inhibitor OST-T315 elevated the phosphorylated MST, LATS1, and YAP levels, and inhibited the mRNA levels of <i>Igfbp4</i> and <i>Ctgf</i> at 44, 48 week-aged mice. OST-T315 also reduced the release of TNF-α, IL-6, IL-1β, and NO, as well as the progression of gastric cancer caused by <i>H. pylori</i> and <i>N</i>-Nitroso-<i>N</i>-methylurea (NMU) treatment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Upon initiation of gastric tumorigenesis signals, <i>H. pylori</i> increases ILK levels and suppresses Hippo signaling, thereby promoting YAP activation and gastric cancer progression. ILK can serve as a potential prevention target to impede <i>H. pylori</i>-induced gastric cancer.</p>\\n </section>\\n </div>\",\"PeriodicalId\":13223,\"journal\":{\"name\":\"Helicobacter\",\"volume\":\"29 4\",\"pages\":\"\"},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Helicobacter\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/hel.13109\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Helicobacter","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/hel.13109","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：整合素连接激酶（ILK）通过调节Hippo-Yes相关蛋白1（YAP）通路对实体瘤至关重要。本研究旨在揭示幽门螺杆菌如何影响 ILK 水平及其在幽门螺杆菌诱发胃癌过程中调控 YAP 的作用：材料：构建了稳定敲除和过表达 Ilk 的 GES-1 细胞和幽门螺杆菌感染的小鼠癌变模型。采用免疫印迹法检测细胞和小鼠中的ILK、磷酸化的哺乳动物STE20样蛋白激酶1（MST1）、大肿瘤抑制因子1（LATS1；S909，T1079）和YAP（S109，S127），以及YAP的荧光强度。通过实时荧光定量PCR、H&E和ELISA检测YAP下游基因Igfbp4和Ctgf、病理变化以及小鼠胃组织中肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和一氧化氮（NO）的水平：结果：在这项研究中，稳定敲除 Ilk 的细胞表现出明显更高的 MST1、LATS1 和 YAP 磷酸化水平，以及 GES-1 细胞核中 YAP 的增加。相反，过表达 Ilk 的细胞则表现出相反的结果。幽门螺杆菌感染导致胃上皮细胞中的ILK水平降低，但胃癌细胞系（MGC803、SGC7901）和小鼠胃癌组织中的ILK水平升高。用 ILK 抑制剂 OST-T315 治疗 44 和 48 周龄小鼠，可提高磷酸化 MST、LATS1 和 YAP 的水平，并抑制 Igfbp4 和 Ctgf 的 mRNA 水平。OST-T315还能减少TNF-α、IL-6、IL-1β和NO的释放，以及幽门螺杆菌和N-亚硝基-N-甲基脲（NMU）治疗引起的胃癌的进展：结论：幽门螺杆菌在启动胃肿瘤发生信号时，会增加ILK水平并抑制Hippo信号转导，从而促进YAP活化和胃癌进展。ILK可作为潜在的预防靶点，阻止幽门螺杆菌诱发胃癌。
Integrin-Linked Kinase in the Development of Gastric Tumors Induced by Helicobacter pylori: Regulation and Prevention Potential
Background
Integrin-linked kinase (ILK) is crucial in solid tumors by regulating the Hippo-Yes-associated protein 1 (YAP) pathway. This study aimed to uncover how Helicobacter pylori influences ILK levels and its role in regulating YAP during H. pylori-induced gastric cancer.
Materials and Methods
GES-1 cells with stable Ilk knockdown and overexpression and a mouse carcinogenesis model for H. pylori infection were constructed. And ILK, the phosphorylated mammalian STE20-like protein kinase 1 (MST1), large tumor suppressor 1 (LATS1; S909, T1079), and YAP (S109, S127) were detected in cells, and mice by western blotting, as well as fluorescence intensity of YAP were assayed by immunofluorescence. YAP downstream genes Igfbp4 and Ctgf, the pathological changes and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β), and nitric oxide (NO) levels in mice gastric tissues were detected by real-time PCR, H&E, and ELISA assays.
Results
In this study, stable Ilk knockdown cells exhibited significantly higher phosphorylated levels of MST1, LATS1, and YAP, as well as increased YAP in the nuclei of GES-1 cells. Conversely, cells with Ilk overexpression showed opposite results. H. pylori infection led to decreased ILK levels in gastric epithelial cells but increased ILK levels in gastric cancer cell lines (MGC803, SGC7901) and gastric cancer tissues in mice. Treatment with the ILK inhibitor OST-T315 elevated the phosphorylated MST, LATS1, and YAP levels, and inhibited the mRNA levels of Igfbp4 and Ctgf at 44, 48 week-aged mice. OST-T315 also reduced the release of TNF-α, IL-6, IL-1β, and NO, as well as the progression of gastric cancer caused by H. pylori and N-Nitroso-N-methylurea (NMU) treatment.
Conclusion
Upon initiation of gastric tumorigenesis signals, H. pylori increases ILK levels and suppresses Hippo signaling, thereby promoting YAP activation and gastric cancer progression. ILK can serve as a potential prevention target to impede H. pylori-induced gastric cancer.
期刊介绍：
Helicobacter is edited by Professor David Y Graham. The editorial and peer review process is an independent process. Whenever there is a conflict of interest, the editor and editorial board will declare their interests and affiliations. Helicobacter recognises the critical role that has been established for Helicobacter pylori in peptic ulcer, gastric adenocarcinoma, and primary gastric lymphoma. As new helicobacter species are now regularly being discovered, Helicobacter covers the entire range of helicobacter research, increasing communication among the fields of gastroenterology; microbiology; vaccine development; laboratory animal science.
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