Deoxycholic acid modulates the progression of gallbladder cancer through N6-methyladenosine-dependent microRNA maturation

Bile acids (BAs), well-defined signaling molecules with diverse metabolic functions, play important roles in cellular processes associated with many cancers. As one of the most common BAs, deoxycholic acid (DCA) is originally synthesized in the liver, stored in the gallbladder, and processed in the...

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Bibliographic Details
Published in:Oncogene 2020-06, Vol.39 (26), p.4983-5000
Main Authors: Lin, Ruirong, Zhan, Ming, Yang, Linhua, Wang, Hui, Shen, Hui, Huang, Shuai, Huang, Xince, Xu, Sunwang, Zhang, Zijie, Li, Weijian, Liu, Qiang, Shi, Yongsheng, Chen, Wei, Yu, Jianxiu, Wang, Jian
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
13/1
13/109
13/51
13/89
13/95
38/109
45/77
45/91
631/337/384
631/67/1504/1329
631/80/86
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AKT protein
Apoptosis
Bile
Bile acids
Cell Biology
Cell proliferation
Deoxycholic acid
Gallbladder
Gallbladder cancer
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
miRNA
Molecular modelling
N6-methyladenosine
Oncology
Post-transcription
PTEN protein
Signal transduction
Tensin
Tumors
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Summary:Bile acids (BAs), well-defined signaling molecules with diverse metabolic functions, play important roles in cellular processes associated with many cancers. As one of the most common BAs, deoxycholic acid (DCA) is originally synthesized in the liver, stored in the gallbladder, and processed in the gut. DCA plays crucial roles in various tumors; however, functions and molecular mechanisms of DCA in gallbladder cancer (GBC) still remain poorly characterized. Here, we analyzed human GBC samples and found that DCA was significantly downregulated in GBC, and reduced levels of DCA was associated with poor clinical outcome in patients with GBC. DCA treatment impeded tumor progression by halting cell proliferation. DCA decreased miR-92b-3p expression in an m 6 A-dependent posttranscriptional modification manner by facilitating dissociation of METTL3 from METTL3–METTL14–WTAP complex, which increased the protein level of the phosphatase and tensin homolog, a newly identified target of miR-92b-3p, and subsequently inactivated the PI3K/AKT signaling pathway. Our findings revealed that DCA might function as a tumor suppressive factor in GBC at least by interfering with miR-92b-3p maturation, and suggested that DCA treatment could provide a new therapeutic strategy for GBC.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-020-1349-6