Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China.
Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, 518036, China.
Arch Toxicol. 2023 Jun;97(6):1627-1647. doi: 10.1007/s00204-023-03501-8. Epub 2023 Apr 30.
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.
肝细胞癌 (HCC) 是一种以高复发率为特征的癌症。克服化疗耐药性可以降低 HCC 的复发率并改善患者的预后。本工作旨在鉴定 HCC 化疗耐药相关的长非编码 RNA（lncRNA），并找到针对鉴定出的 lncRNA 的有效药物，以改善化疗耐药性。在这项研究中，基于癌症基因组图谱的生物信息学分析揭示了一个新的化疗耐药指数，并提出 LINC02331 作为与 HCC 化疗耐药性和患者预后相关的 lncRNA，作为独立的预后指标。此外，LINC02331 通过调节 Wnt/β-catenin 信号通路促进 DNA 损伤修复、DNA 复制和上皮间质转化，同时减弱细胞周期阻滞和细胞凋亡，从而刺激 HCC 对顺铂细胞毒性、增殖和转移的耐药性。有趣的是，我们开发了一种新的氧化偶联方法来合成二聚体氧化小檗碱 CT4-1，它通过体内小鼠模型测量，没有明显的副作用，表现出优异的抗 HCC 活性，并且可以下调 LINC02331 ，可以通过抑制 Wnt/β-catenin 信号通路来减轻 LINC02331 诱导的 HCC 进展。RNA 测序分析验证了 CT4-1 影响差异表达基因在失调途径和过程中的参与，包括 Wnt、DNA 损伤修复、细胞周期、DNA 复制、细胞凋亡和细胞粘附分子。此外，基于 CT4-1 处理的癌细胞和公共癌症数据库中的 RNA 测序数据构建的预测模型，证明 CT4-1 是一种有效的细胞毒性药物，可改善 HCC 患者的预后。总之，与 HCC 化疗耐药相关的 LINC02331 通过促进对顺铂细胞毒性、增殖和转移的耐药性，独立预测患者预后不良并促进 HCC 进展。二聚体氧化小檗碱 CT4-1 靶向 LINC02331，与顺铂具有协同细胞毒性，可减轻 HCC 进展并改善患者预后。我们的研究确定 LINC02331 为替代靶标，并提出 CT4-1 作为 HCC 治疗的有效细胞毒性药物。
