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.
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The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
We are very grateful for the equipment and technical support provided by The Second Affiliated Hospital of Xi’an Jiaotong University.
Funding
This work was supported by the Basic and Applied Research Promotion Engineering/Medical Research Project of Xi’an Science and Technology Plan (No. 21YXYJ0118), the General Project in the Field of Social Development of Shaanxi Provincial Department of Science and Technology: the research on the mechanism and potential clinical significance of new long chain non coding RNA AC006262.5 in promoting hepatocellular carcinogenesis (NO. 2020SF-065) and the General Project of Key Research and Development Projects of Shaanxi Province: the experimental study of EGCG against liver fibrosis through miR-1207-5p (NO. 2021SF-224).
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FC, JJ, and GZ: designed the experiments; FC and JJ: wrote the manuscript; DL, LD and HL: performed the experiments; YS, YZ, JW and YQ: analyzed the data, GZ: revised the manuscript. All the authors have read and approved the final version of the manuscript.
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Chen, F., Jiang, J., Liu, D. et al. The lncRNA lnc-TSI antagonizes sorafenib resistance in hepatocellular carcinoma via downregulating miR-4726-5p expression and upregulating KCNMA1 expression. J Mol Histol 55, 83–96 (2024). https://doi.org/10.1007/s10735-023-10173-2
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DOI: https://doi.org/10.1007/s10735-023-10173-2