Abstract
Hepatocellular carcinoma (HCC) is a type of cancer characterized by high recurrence rates. Overcoming chemoresistance can reduce HCC recurrence and improve patients’ prognosis. This work aimed to identify HCC chemoresistance-associated long non-coding RNA (lncRNA) and find an effective drug targeting the identified lncRNA for ameliorating the chemoresistance. In this investigation, bioinformatics analysis based on The Cancer Genome Atlas revealed a new chemoresistance index and suggested LINC02331 as an HCC chemoresistance and patients’ prognosis-associated lncRNA that served as an independent prognostic indicator. Moreover, LINC02331 promoted DNA damage repair, DNA replication, and epithelial-mesenchymal transition as well as attenuated cell cycle arrest and apoptosis through regulating Wnt/β-catenin signaling, thus stimulating HCC resistance to cisplatin cytotoxicity, proliferation, and metastasis. Interestingly, we developed a novel oxidative coupling approach to synthesize a dimeric oxyberberine CT4-1, which exerted superior anti-HCC activities without obvious side effects measured by in vivo mice model and could downregulate LINC02331 mice model and could downregulate LINC02331 to mitigate LINC02331-induced HCC progression by suppressing Wnt/β-catenin signaling. RNA sequencing analyses verified the involvement of CT4-1-affected differential expression genes in dysregulated pathways and processes, including Wnt, DNA damage repair, cell cycle, DNA replication, apoptosis, and cell adhesion molecules. Furthermore, CT4-1 was demonstrated to be an effective cytotoxic drug in ameliorating HCC patients’ prognosis with a prediction model constructed based on RNA-sequencing data from CT4-1-treated cancer cells and public cancer database. In summary, HCC chemoresistance-associated LINC02331 independently predicted poor patients’ prognosis and enhanced HCC progression by promoting resistance to cisplatin cytotoxicity, proliferation, and metastasis. Targeting LINC02331 by the dimeric oxyberberine CT4-1 that exhibited synergistic cytotoxicity with cisplatin could alleviate HCC progression and improve patients’ prognosis. Our study identified LINC02331 as an alternative target and suggested CT4-1 as an effective cytotoxic drug in HCC treatment.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This study was funded by China Postdoctoral Science Foundation (No. 2021T140468), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515111089), Key Discipline Construction Project of Guangdong Medical University (No. 4SG22004G), Medical Scientific Research Foundation of Guangdong Province, China (No. A2022042), Guangdong Basic and Applied Basic Research Foundation (No. 2021B1515140027), Dongguan Social science and Technology Development (Key) Project (No. 20221800905582), Funds for Ph.D. researchers of Guangdong Medical University in 2022 (No. 4SG22226G).
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XL: Funding acquisition. XL and JC: Conceptualization, Methodology, Investigation, Writing-Original Draft. XL, DC, YG, and YD: Methodology and Investigation. DY: Project administration. ZH: Project administration and Funding acquisition. CT: Supervision, Funding acquisition, Project administration. All authors participated in editing the manuscript.
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Lin, X., Chen, J., Li, X. et al. Dimeric oxyberberine CT4-1 targets LINC02331 to induce cytotoxicity and inhibit chemoresistance via suppressing Wnt/β-catenin signaling in hepatocellular carcinoma. Arch Toxicol 97, 1627–1647 (2023). https://doi.org/10.1007/s00204-023-03501-8
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DOI: https://doi.org/10.1007/s00204-023-03501-8