Upregulation of oncogene Activin A receptor type I by Helicobacter pylori infection promotes gastric intestinal metaplasia via regulating CDX2.

Abstract

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 ACVR1knockout 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/BL6models 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 ACVR1knockout 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 ACVR1knockout. 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.