TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression

Zhen, Ni; Min, Yali; Han, Cheng-Bo; Tan, Yuan; Lu, Wenquan; Ashktorab, Hassan; Smoot, Duane T.; Wu, Qiong; Wu, Jian; Zeng, Wei‐Zheng; Shi, Yongquan

doi:10.1038/s41420-020-0290-3

Cited by 22 publications

(19 citation statements)

References 57 publications

(65 reference statements)

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“…BAs can enhance caudal-related homeobox family 2 (CDX2) and mucin 2 (MUC2) expression via FXR/NF-κB signaling [ 176 , 177 ] and cyclooxygenase-2 (COX-2) expression via induction of SHP [ 178 ], all promoting gastric intestinal metaplasia. Acidic bile salts can induce telomerase activity in a c-Myc-dependent fashion [ 179 , 180 ], while DCA can induce the metaplastic phenotype of gastric cancer cells [ 181 ] (see Tables 6 and 7 ). TGR5 is a key factor in BA-induced gastric metaplasia via HNF4α [ 181 ], EGFR and mitogen-activated protein kinase (MAPK) [ 182 ] activation and promotes EMT in gastric carcinoma cells [ 183 ].…”

Section: Effects Of Bile Acids In Cancersmentioning

confidence: 99%

“…Acidic bile salts can induce telomerase activity in a c-Myc-dependent fashion [ 179 , 180 ], while DCA can induce the metaplastic phenotype of gastric cancer cells [ 181 ] (see Tables 6 and 7 ). TGR5 is a key factor in BA-induced gastric metaplasia via HNF4α [ 181 ], EGFR and mitogen-activated protein kinase (MAPK) [ 182 ] activation and promotes EMT in gastric carcinoma cells [ 183 ]. TGR5 is overexpressed in gastrointestinal adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival [ 184 ].…”

Section: Effects Of Bile Acids In Cancersmentioning

confidence: 99%

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The role of bile acids in carcinogenesis

Režen

Rozman

Kovàcs

et al. 2022

Cell. Mol. Life Sci.

144

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Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.

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Section: Effects Of Bile Acids In Cancersmentioning

confidence: 99%

Section: Effects Of Bile Acids In Cancersmentioning

confidence: 99%

The role of bile acids in carcinogenesis

Režen

Rozman

Kovàcs

et al. 2022

Cell. Mol. Life Sci.

144

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“…5,6 However, it is noteworthy that both gastric IM and Barrett's metaplasia of the esophagus, another type of IM, are the result of bile acid reflux. 7,8 This strongly suggests a key regulatory role of bile acid reflux in IM.…”

Section: Introductionmentioning

confidence: 97%

Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia

Yue

Cui

Zheng

et al. 2021

Molecular Therapy - Nucleic Acids

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Bile acid reflux and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), a precursor of gastric cancer; however, the mechanism underlying this phenomenon is unclear. Here, we demonstrate that alkylation repair homolog protein 5 (ALKBH5), a major RNA N 6 -adenosine demethylase, is required for bile acid-induced gastric IM. Mechanistically, we revealed the N 6 -methyladenosine (m 6 A) modification profile in gastric IM for the first time and identified ZNF333 as a novel m 6 A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m 6 A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/ CYLD axis and activating NF-kB signaling. Reciprocally, p65, the key transcription factor of the canonical NF-kB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feedforward circuit. Furthermore, ALKBH5 levels were positively correlated with ZNF333 and CDX2 levels in IM tissues, indicating significant clinical relevance. Collectively, our findings suggest that an m 6 A modification-associated positive feedforward loop between ALKBH5 and NF-kB signaling is involved in generating the IM phenotype of gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.

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“…In adults, HNF4α is expressed in the colon and small intestine, not in the gastric mucosa, but HNF4α mediated by the P1 promoter can be observed in gastric IM tissues [ 41 ]. Zhen et al found that bile reflux activated the TGR5–ERK1/2 pathway after induction of HNF4α expression, thus upregulating the expression of CDX2 [ 42 ]. Wang et al found that bile acids promoted the development of gastric IM through HNF4a/HDCA6/CDX2 pathway in vivo and in vitro [ 43 ].…”

Section: Mechanism Of Gastric Im Induced By Bile Acidmentioning

confidence: 99%

“… [ 109 ] DCA TGR5 tissues, cell lines BAs treatment could activate TGR5–ERK1/2 pathway following induction of HNF4α expression, which further promoted metaplasia markers expression through direct regulation of KLF4 and CDX2. [ 42 ] …”

Section: Bile Acid Receptorsmentioning

confidence: 99%

Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review

Liu

Wei

et al. 2022

Cell Death Discov.

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Gastric intestinal metaplasia (IM) is a precancerous lesion that increases the risk of subsequent gastric cancer (GC) development. Therefore, the mechanism of IM has been the focus of basic and clinical research. Helicobacter pylori (H. pylori) infection has been recognized as the main pathogenesis of gastric IM. However, more and more studies have shown that chronic inflammation of gastric mucosa caused by bile reflux is the key pathogenic factor of gastric IM. Bile reflux activates the expression of IM biomarkers via the bile acid receptor. In addition, microRNAs, exosomes, and epigenetics are also involved in the occurrence and development of bile acid-induced gastric IM. Currently, the relevant research is still very few. The molecular mechanism of the phenotypic transformation of gastrointestinal epithelial cells induced by bile acids has not been fully understood. This article mainly reviews the physiology and pathology of bile acid, mechanism of gastric IM induced by bile acid, bile acid receptors, and so on, in order to provide reference for further research.

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TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression

Cited by 22 publications

References 57 publications

The role of bile acids in carcinogenesis

The role of bile acids in carcinogenesis

Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia

Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review

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