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ADAR1 promotes cisplatin resistance in intrahepatic cholangiocarcinoma by regulating BRCA2 expression through A-to-I editing manner.
- Source :
-
Cell proliferation [Cell Prolif] 2024 Oct; Vol. 57 (10), pp. e13659. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
-
Abstract
- Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.<br /> (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)
- Subjects :
- Humans
Cell Line, Tumor
Gene Expression Regulation, Neoplastic drug effects
Female
Animals
MicroRNAs genetics
MicroRNAs metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Male
Cisplatin pharmacology
Cisplatin therapeutic use
Cholangiocarcinoma genetics
Cholangiocarcinoma drug therapy
Cholangiocarcinoma metabolism
Cholangiocarcinoma pathology
Drug Resistance, Neoplasm genetics
BRCA2 Protein metabolism
BRCA2 Protein genetics
Adenosine Deaminase metabolism
Adenosine Deaminase genetics
RNA-Binding Proteins metabolism
RNA-Binding Proteins genetics
Bile Duct Neoplasms metabolism
Bile Duct Neoplasms genetics
Bile Duct Neoplasms drug therapy
Bile Duct Neoplasms pathology
RNA Editing
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2184
- Volume :
- 57
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell proliferation
- Publication Type :
- Academic Journal
- Accession number :
- 38773866
- Full Text :
- https://doi.org/10.1111/cpr.13659