Wang Zongwen, Zhu Qiankun, Li Xiaodong, Ren Xiaohang, Li Jingtao, Zhang Yao, Zeng Shicong, Xu Lishan, Dong Xiaoqun, Zhai Bo
Department of Surgical Oncology and Hepatobiliary Surgery, The Fourth Affiliated Hospital of Harbin Medical University Harbin 150001, Heilongjiang, China.
The Liver Research Center of Rhode Island Hospital/Lifespan; Department of Medicine, The Warren Alpert Medical School of Brown University Providence, RI 02903, USA.
Am J Cancer Res. 2022 Sep 15;12(9):4343-4360. eCollection 2022.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death attributed to high frequency of metastasis and multiple drug resistance. We aim to examine the underlying molecular mechanism and to seek potential strategies to reverse primary/acquired resistance to regorafenib. Topoisomerase IIα (TOP2A) is critical for tumorigenesis and carcinogenesis. Clinically, high-TOP2A expression was correlated to shorter overall survival (OS) of patients, but its role in drug resistance of HCC remains unknown. Here, we screened the expression profiling of TOP2A in HCC and identified TOP2A as an upregulated gene involved in the resistance to regorafenib. Sustained exposure of HCC cells to regorafenib could upregulate the expression of TOP2A. Silencing TOP2A enhanced HCC cells' sensitivity to regorafenib. TOP2A inhibition by doxorubicin or epirubicin synergized with regorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant features both and . Thus, targeting TOP2A may be a promising therapeutic strategy to alleviate resistance to regorafenib and thus improving the efficacy of HCC treatment.
肝细胞癌（HCC）是癌症相关死亡的第三大主要原因，这归因于其高转移频率和多药耐药性。我们旨在研究其潜在的分子机制，并寻找逆转对瑞戈非尼原发性/获得性耐药的潜在策略。拓扑异构酶IIα（TOP2A）对肿瘤发生和癌变至关重要。在临床上，TOP2A高表达与患者较短的总生存期（OS）相关，但其在HCC耐药中的作用尚不清楚。在此，我们筛选了HCC中TOP2A的表达谱，并确定TOP2A是一个与对瑞戈非尼耐药相关的上调基因。将HCC细胞持续暴露于瑞戈非尼可上调TOP2A的表达。沉默TOP2A可增强HCC细胞对瑞戈非尼的敏感性。阿霉素或表柔比星对TOP2A的抑制作用与瑞戈非尼协同，可抑制具有索拉非尼耐药特征的索拉非尼耐药HCC肿瘤的生长。因此，靶向TOP2A可能是一种有前景的治疗策略，可减轻对瑞戈非尼的耐药性，从而提高HCC治疗的疗效。
