Long non-coding RNA PVT1 mediates bile acid-induced gastric intestinal metaplasia via a miR-34b-5p/HNF4α positive feedback loop.
10.1097/CM9.0000000000003621
- Author:
Kexin LIN
1
;
Nuo YAO
1
;
Xingyu ZHAO
1
;
Xiaodong QU
1
;
Xuezhi LI
1
;
Songbo LI
1
;
Shiyue LUO
1
;
Min CHEN
1
;
Na WANG
1
;
Yongquan SHI
1
Author Information
1. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xi'an, Shaanxi 710032, China.
- Publication Type:Journal Article
- Keywords:
Bile acids;
Gastric intestinal metaplasia;
Long non-coding RNAs
- MeSH:
Humans;
RNA, Long Noncoding/metabolism*;
MicroRNAs/metabolism*;
Hepatocyte Nuclear Factor 4/genetics*;
Bile Acids and Salts;
Kruppel-Like Factor 4;
Metaplasia/metabolism*
- From:
Chinese Medical Journal
2025;138(18):2324-2335
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Bile acids (BAs) facilitate the progression of gastric intestinal metaplasia (GIM). Long non-coding RNAs (lncRNAs) dysregulation was observed along with the initiation of gastric cancer. However, how lncRNAs function in GIM remains unclear. This study aimed to explore the role and mechanism of lncRNA PVT1 in GIM, and provide a potential therapeutic target for GIM treatment.
METHODS:We employed RNA sequencing (RNA-seq) to screen dysregulated lncRNAs in gastric epithelial cells after BA treatment. Bioinformatics analysis was conducted to reveal the regulatory mechanism. PVT1 expression was detected in 21 paired biopsies obtained under endoscopy. Overexpressed and knockdown cell models were established to explore gene functions in GIM. Molecular interactions were validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (Ch-IP). The levels of relative molecular expression were detected in GIM tissues.
RESULTS:We confirmed that lncRNA PVT1 was upregulated in BA-induced GIM model. PVT1 promoted the expression of intestinal markers such as CDX2 , KLF4 , and HNF4α . Bioinformatics analysis revealed that miR-34b-5p was a putative target of PVT1 . miR-34b-5p mimics increased CDX2 , KLF4 , and HNF4α levels. Restoration of miR-34b-5p decreased the pro-metaplastic effect of PVT1 . The interactions between PVT1 , miR-34b-5p, and the downstream target HNF4α were validated. Moreover, HNF4α could transcriptionally activated PVT1 , sustaining the GIM phenotype. Finally, the activation of the PVT1 /miR-34b-5p/ HNF4α loop was detected in GIM tissues.
CONCLUSIONS:BAs facilitate GIM partially via a PVT1/miR-34b-5p/HNF4α positive feedback loop. PVT1 may become a novel target for blocking the continuous development of GIM and preventing the initiation of gastric cancer in patients with bile reflux.
