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The lncRNA lnc-TSI antagonizes sorafenib resistance in hepatocellular carcinoma via downregulating miR-4726-5p expression and upregulating KCNMA1 expression.
- Source :
-
Journal of molecular histology [J Mol Histol] 2024 Feb; Vol. 55 (1), pp. 83-96. Date of Electronic Publication: 2024 Jan 02. - Publication Year :
- 2024
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Abstract
- Acquired drug resistance is a main reason for limiting the application of sorafenib in HCC treatment. This study aimed to explore the role and mechanisms of a novel long non-coding RNA (lncRNA), lnc-TSI, in sorafenib resistance of HCC. The interaction between lnc-TSI and miR-4726-5p, and miR-4726-5p and KCNMA1 were predicted using bioinformatic tools. Expression of the molecules in the lnc-TSI/miR-4726-5p/KCNMA1 axis in clinical samples and cell lines, as well as the sorafenib resistant HCC cell lines, was determined using qRT-PCR or western blotting. Expressions of lnc-TSI, miR-4726-5p, and KCNMA1 were manipulated in HepG2 and Huh7 cells through plasmid transfection or lentivirus infection. The CCK-8, flow cytometry, and Tunel assays were employed to determine the role of this axis on sorafenib resistance of HCC. A xenograft model was established using sorafenib-resistant HepG2 and Huh7 cells followed by in vivo sorafenib treatments to confirm the in vitro findings. Lnc-TSI and KCNMA1 expressions were significantly downregulated in HCC clinical samples and cell lines, especially in sorafenib resistance ones, while mi-4726-5p presented a reversed expression pattern. Lnc-TSI interacted with miR-4726-5p, and Lnc-TSI acts as a ceRNA via sponging miR-4726-5p in HCC cells. Overexpression of lnc-TSI and KCNMA1 promoted apoptosis and decreased cell viability of sorafenib-treated HCC cells, thus alleviated sorafenib resistance. miR-4726-5p mimic reversed the KCNMA1-mediated sorafenib sensitivity-promoting effect, while additional overexpression of lnc-TSI reversed the effect of miR-4726-5p. In vivo analysis also showed that overexpression of ln-TSI diminished sorafenib resistance in mice inoculated with sorafenib-resistant HCC cells via increasing KCNMA1 expression and decreasing miR-4726-5p expression. The lnc-TSI/miR-4726-5p/KCNMA1 axis plays a critical role in regulating the resistance of HCC to sorafenib, and might serve as a therapeutic target to manage sorafenib resistance of HCC in clinic.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)
- Subjects :
- Humans
Animals
Mice
Sorafenib pharmacology
Cell Line, Tumor
Cell Proliferation genetics
Gene Expression Regulation, Neoplastic
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits genetics
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits metabolism
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular genetics
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Liver Neoplasms drug therapy
Liver Neoplasms genetics
Liver Neoplasms metabolism
MicroRNAs genetics
MicroRNAs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1567-2387
- Volume :
- 55
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of molecular histology
- Publication Type :
- Academic Journal
- Accession number :
- 38165571
- Full Text :
- https://doi.org/10.1007/s10735-023-10173-2