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Deoxycholic acid modulates the progression of gallbladder cancer through N 6 -methyladenosine-dependent microRNA maturation.
- Source :
-
Oncogene [Oncogene] 2020 Jun; Vol. 39 (26), pp. 4983-5000. Date of Electronic Publication: 2020 Jun 08. - Publication Year :
- 2020
-
Abstract
- 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 <superscript>6</superscript> 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.
- Subjects :
- Adenosine metabolism
Animals
Cell Line, Tumor
Cell Proliferation genetics
Deoxycholic Acid metabolism
Disease Progression
Gallbladder Neoplasms metabolism
Gallbladder Neoplasms therapy
HEK293 Cells
Humans
Male
Mice, Inbred BALB C
Mice, Nude
RNA Interference
Xenograft Model Antitumor Assays methods
Adenosine analogs & derivatives
Cell Proliferation drug effects
Deoxycholic Acid pharmacology
Gallbladder Neoplasms genetics
Gene Expression Regulation, Neoplastic drug effects
MicroRNAs genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 39
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 32514152
- Full Text :
- https://doi.org/10.1038/s41388-020-1349-6