Abstract
BackgroundGastric intestinal metaplasia (IM) is considered a precancerous lesion, and bile acids (BA) play a critical role in the induction of IM. Ectopic expression of HNF4α 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.MethodsThe effects of HNF4α 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.ResultsThe transgenic mouse model validated that HNF4α stimulated the HDAC6 expression and mucin secretion in gastric mucosa. Increased HDAC6 and HNF4α expression was also detected in the gastric IM cell model and patient specimens. HNF4α could bind to and activate HDAC6 promoter. In turn, HDAC6 enhanced the HNF4α protein level in GES-1 cells. Furthermore, miR-1 suppressed the expression of downstream intestinal markers by targeting HDAC6 and HNF4α.ConclusionsOur findings show that the HDAC6/HNF4α 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).
Highlights
Gastric cancer (GC) is the third leading cause of cancerrelated death worldwide [1]
Cells were stimulated with various concentrations of the deoxycholic acid (DCA) or vehicle alone for 24 h, protein was extracted and subjected to western blot analysis for histone deacetylase 6 (HDAC6), hepatocyte nuclear factor-4α (HNF4α), Caudal-related homeobox transcription factor 2 (CDX2), MUCIN 2 (MUC2), Krüppel-like factor 4 (KLF4) and β-actin. β-Actin levels were used as internal control in immunoblots. d, e DCA (100 μM) enhanced the protein levels of HDAC6, HNF4α and intestinal markers in primary gastric epithelial cells
Overlapping expression of the two molecules was seen in 80.67% (96/119) of intestinal metaplasia (IM) tissues, which further suggested a close correlation between HDAC6 and HNF4α (Fig. 3g and Tables 4, 5)
Summary
Gastric cancer (GC) is the third leading cause of cancerrelated death worldwide [1]. Universally, the occurrence and stepwise development of intestinal gastric cancer (IGC) follow the Correa model: superficial gastritis–atrophic gastritis–metaplasia–hyperplasia–cancer [2, 3]. 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 HNF4α was observed in a BA-induced IM cell model. Methods The effects of HNF4α 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). Results The transgenic mouse model validated that HNF4α stimulated the HDAC6 expression and mucin secretion in gastric mucosa. Increased HDAC6 and HNF4α expression was detected in the gastric IM cell model and patient specimens. MiR-1 suppressed the expression of downstream intestinal markers by targeting HDAC6 and HNF4α. Conclusions Our findings show that the HDAC6/HNF4α 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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