Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Helicobacter. 2021 Dec;26(6):e12849. doi: 10.1111/hel.12849. Epub 2021 Sep 7.
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.
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.
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).
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.
激活素 A 受体 I 型（ACVR1）参与肿瘤发生。然而，ACVR1 在胃癌（GC）中的潜在分子机制及其与幽门螺杆菌的关联仍不清楚。
利用癌症基因组图谱（TCGA）和基因表达谱交互式分析（GEPIA）数据库探讨 GC 中 ACVR1 的表达及其与生存的关系。使用 CRISPR/Cas-9 敲除 ACVR1；在 AGS 细胞中进行 RNA 测序分析，敲除 ACVR1 和正常对照。进行 CCK-8、集落形成和 Transwell 测定等功能实验，以证明 ACVR1 在细胞增殖、侵袭和转移中的作用。建立 H. pylori 感染的 C57/BL6 模型。检测 H. pylori 菌株共培养的 AGS 细胞中的 ACVR1、p-Smad1/5 和 CDX2。检测敲除 ACVR1 和正常对照的 AGS 细胞中的 CDX2 和 BMP 信号通路的关键元件。此外，进行免疫组织化学检测胃组织中 ACVR1 和 CDX2 的表达。
来自 TCGA、GEPIA 和我院收集的样本显示，GC 中 ACVR1 的表达高于正常对照（p<0.05）。ACVR1 促进体外细胞增殖、迁移和侵袭。cagA 和 cagA H. pylori 均可上调 ACVR1 的表达（p<0.05）。下调 ACVR1 抑制了 H. pylori 诱导的细胞增殖、迁移和侵袭（p<0.05）。H. pylori 增加了 p-Smad 1/5 和 CDX2 的表达。敲除 ACVR1 后，AGS 细胞中 CDX2 和 BMP 信号通路的关键元件下调。在肠上皮化生（IM）阶段，ACVR1 和 CDX2 上调。此外，H. pylori 阳性组的 ACVR1 和 CDX2 表达高于 H. pylori 阴性组（p<0.05）。
我们的数据表明，H. pylori 感染增加 ACVR1 的表达，通过调节 CDX2 促进胃 IM，这是 H. pylori 致癌作用的关键步骤。
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