Li Meng, Zhang Lixing, Ge Chao, Chen Lijuan, Fang Tao, Li Hong, Tian Hua, Liu Junxi, Chen Taoyang, Jiang Guoping, Xie Haiyang, Cui Ying, Yao Ming, Li Jinjun
School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, China.
State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Oncotarget. 2015 Sep 22;6(28):25149-60. doi: 10.18632/oncotarget.4438.
In our previous studies, we reported that CD133(+) cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133(+) CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133(+) subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133(+) CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC.
在我们之前的研究中，我们报道了CD133(+)癌干细胞（CSCs）在肝细胞癌（HCC）中具有化疗抗性，并且异紫堇碱处理降低了CD133(+) CSCs的比例。在此，我们发现异紫堇碱衍生物（d-ICD）抑制HCC细胞生长，特别是在CD133(+)亚群中，并使HCC细胞对索拉非尼治疗更敏感。d-ICD以时间依赖性方式抑制IGF2BP3表达，并且IGF2BP3表达与d-ICD诱导的生长抑制呈负相关。IGF2BP3过表达富集了HCC中的CD133(+) CSC亚群，增强了肿瘤球形成，并抑制了索拉非尼和阿霉素的细胞毒性作用。IGF2BP3过表达后，包括ABCB1和ABCG2在内的耐药相关基因的表达以及CSC标志物CD133的表达增加。我们的研究结果强调了这些观察结果的重要性，即高IGF2BP3表达预示着236例HCC患者队列的不良生存，并且在体内与ABCG2和CD133表达呈正相关。这些结果表明，d-ICD可能通过降低IGF2BP3来抑制HCC细胞生长，并且IGF2BP3可能作为HCC的治疗靶点。
