Journal
GASTRIC CANCER
Volume 24, Issue 1, Pages 103-116Publisher
SPRINGER
DOI: 10.1007/s10120-020-01108-x
Keywords
Gastric intestinal metaplasia; HDAC6; HNF4 alpha; CDX2; Gastric cancer
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Funding
- National Natural Science Foundation of China [81873554]
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The HDAC6/HNF4 alpha loop regulated by miR-1 plays a critical role in gastric intestinal metaplasia (IM). Blocking the activation of this loop could be a potential approach to preventing BA-induced gastric IM or even gastric cancer (GC).
Background Gastric intestinal metaplasia (IM) is considered a precancerous lesion, and bile acids (BA) play a critical role in the induction of IM. Ectopic expression of HNF4 alpha was observed in a BA-induced IM cell model. However, the mechanisms underlying the upregulation of the protein in IM cells remains to be elucidated. Methods The effects of HNF4 alpha on gastric mucosal cells in vivo were identified by a transgenic mouse model and RNA-seq was used to screen downstream targets of deoxycholic acid (DCA). The expression of pivotal molecules and miR-1 was detected by immunohistochemistry and in situ hybridization in normal, gastritis and IM tissue slides or microarrays. The transcriptional regulation of HDAC6 was investigated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Results The transgenic mouse model validated that HNF4 alpha stimulated the HDAC6 expression and mucin secretion in gastric mucosa. Increased HDAC6 and HNF4 alpha expression was also detected in the gastric IM cell model and patient specimens. HNF4 alpha could bind to and activate HDAC6 promoter. In turn, HDAC6 enhanced the HNF4 alpha protein level in GES-1 cells. Furthermore, miR-1 suppressed the expression of downstream intestinal markers by targeting HDAC6 and HNF4 alpha. Conclusions Our findings show that the HDAC6/HNF4 alpha loop regulated by miR-1 plays a critical role in gastric IM. Blocking the activation of this loop could be a potential approach to preventing BA-induced gastric IM or even gastric cancer (GC).
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