Upregulation of oncogene Activin A receptor type I by Helicobacter pylori infection promotes gastric intestinal metaplasia via regulating CDX2
Upregulation of oncogene Activin A receptor type I by Helicobacter pylori infection promotes gastric intestinal metaplasia via regulating CDX2
复制标题
幽门螺杆菌感染上调原癌基因激活素A型受体促进胃肠上皮化生
DOI：
10.1111/hel.12849
复制
发表时间：
2021-09-07
期刊：
影响因子：
4.4
通讯作者：
Zhu, Yin
中科院分区：
文献类型：
--
作者：
Chen, Hong-Yan;Hu, Yi;Zhu, Yin
研究背景激活素A受体I型(ACVR1)参与肿瘤的发生。然而，ACVR1在胃癌中的潜在分子机制及其与幽门螺杆菌的关系尚不清楚。材料与方法利用肿瘤基因组图谱(TCGA)和基因表达谱交互分析(GEPIA)数据库，研究ACVR1在胃癌和正常对照中的表达及其与生存的关系。用CRISPR/Cas-9基因敲除ACVR1基因；对ACVR1基因敲除的AGS细胞和正常对照细胞进行RNA测序分析。功能实验(CCK-8、集落形成和Transwell实验)证实ACVR1在细胞增殖、侵袭和转移中的作用。建立幽门螺杆菌感染C57/BL6小鼠模型。在与幽门螺杆菌共培养的AGS细胞中检测到ACVR1、p-Smad1/5和CDX2。在ACVR1基因敲除的AGS细胞和正常对照细胞中检测CDX2和BMP信号通路的关键元件。免疫组织化学方法检测ACVR1和CDX2在胃组织中的表达。结果TCGA、GEPIA及本院采集的标本中，胃癌组织中ACVR1的表达均高于正常对照组(p<；0.05)。ACVR1在体外可促进细胞的增殖、迁移和侵袭。CagA(+)和cagA(-)幽门螺杆菌均可上调ACVR1的表达(p<0.05)。ACVR1的下调抑制了幽门螺杆菌诱导的细胞增殖、迁移和侵袭(p<；0.05)。幽门螺杆菌可增加p-Smad1/5和CDX2的表达。在ACVR1基因敲除的AGS细胞中，CDX2和BMP信号通路的关键元件下调。ACVR1和CDX2在肠化生期表达上调。Hp阳性组ACVR1和CDX2表达高于Hp阴性组(P<0.05)。结论幽门螺杆菌感染可增加ACVR1的表达，通过调节CDX2促进胃IM，这是幽门螺杆菌致癌的重要环节。
Background Activin A receptor type I (ACVR1) is involved in tumorigenesis. However, the underlying molecular mechanisms of ACVR1 in gastric cancer (GC) and its association with Helicobacter pylori remained unclear. Materials and methods The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database were utilized to explore the ACVR1 expression in GC and normal control and its association with survival. The ACVR1 was knocked out using CRISPR/Cas-9; RNA sequencing analysis was performed in AGS cells with ACVR1 knockout and normal control. Functional experiments (CCK-8, colony-forming, and transwell assays) were conducted to demonstrate the role of ACVR1 in cell proliferation, invasion, and metastasis. H. pylori-infected C57/BL6 models were established. ACVR1, p-Smad1/5, and CDX2 were detected in AGS cells cocultured with H. pylori strains. The CDX2 and key elements of BMP signaling pathway were detected in AGS cells with ACVR1 knockout and normal control. In addition, Immunohistochemistry was performed to detect the ACVR1 and CDX2 expression in gastric samples. Results ACVR1 expression was higher in GC than normal control from TCGA, GEPIA, and samples collected from our hospital (p < 0.05). ACVR1 promoted cell proliferation, migration, and invasion in vitro. Both cagA(+) and cagA(-) H. pylori could upregulate the expression ACVR1 (p < 0.05). Downregulation of ACVR1 inhibited the H. pylori-induced cell proliferation, migration, and invasion (p < 0.05). H. pylori increased the expression of p-Smad 1/5 and CDX2. The CDX2 and key elements of BMP signaling pathway were downregulated in AGS cells with ACVR1 knockout. ACVR1 and CDX2 were upregulated in the stage of intestinal metaplasia (IM). Moreover, ACVR1 and CDX2 expressions were higher in H. pylori-positive group than H. pylori-negative group (p < 0.05). Conclusion Our data indicate that H. pylori infection increases ACVR1 expression, promoting gastric IM via regulating CDX2, which is an essential step in H. pylori carcinogenesis.