Cai Shijiao, Bi Zhun, Bai Yunpeng, Zhang Heng, Zhai Denghui, Xiao Cui, Tang Yuanhao, Yang Lan, Zhang Xiaoyun, Li Kun, Yang Ru, Liu Yanrong, Chen Shuang, Sun Tao, Liu Huijuan, Yang Cheng
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Front Oncol. 2020 Jan 9;9:1431. doi: 10.3389/fonc.2019.01431. eCollection 2019.
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with poor prognosis and high incidence. Cancer stem cells play a vital role in tumor initiation and malignancy. The degree of differentiation of HCC is closely related to its stemness. Glycyrrhizic acid (GA) plays a critical role in inhibiting the degree of malignancy of HCC. At present, the effect of GA on the differentiation and stemness of HCC has not been reported, and its pharmacological mechanism remains to be elucidated. This study evaluated the effect of GA on the stemness of HCC and investigated its targets through proteomics and chemical biology. Results showed that GA can repress stemness and induce differentiation in HCC . GEO analysis revealed that cell differentiation and stem cell pluripotency were up-regulated and down-regulated after GA administration, respectively. Virtual screening was used to predict the c-Jun N-terminal kinase 1 (JNK1) as a direct target of GA. Moreover, chemical biology was used to verify the interaction of JNK1 and GA. Experimental data further indicated that JNK1 inhibits stemness and induces differentiation of HCC. GA exerts its function by targeting JNK1. Clinical data analysis from The Cancer Genome Atlas also revealed that JNK1 can aggravate the degree of malignancy of HCC. The results indicated that, by targeting JNK1, GA can inhibit tumor growth through inducing differentiation and repressing stemness. Furthermore, GA enhanced the anti-tumor effects of sorafenib in HCC treatment. These results broadened our insight into the pharmacological mechanism of GA and the importance of JNK1 as a therapeutic target for HCC treatment.
肝细胞癌（HCC）是最常见的恶性肿瘤之一，预后较差且发病率高。癌症干细胞在肿瘤起始和恶性肿瘤形成中起着至关重要的作用。HCC的分化程度与其干性密切相关。甘草酸（GA）在抑制HCC的恶性程度方面起着关键作用。目前，GA对HCC分化和干性的影响尚未见报道，其药理机制仍有待阐明。本研究评估了GA对HCC干性的影响，并通过蛋白质组学和化学生物学研究其靶点。结果表明，GA可抑制HCC的干性并诱导其分化。基因表达综合数据库（GEO）分析显示，给予GA后细胞分化和干细胞多能性分别上调和下调。虚拟筛选预测c-Jun氨基末端激酶1（JNK1）为GA的直接靶点。此外，利用化学生物学验证JNK1与GA的相互作用。实验数据进一步表明，JNK1抑制HCC的干性并诱导其分化。GA通过靶向JNK1发挥其功能。来自癌症基因组图谱的临床数据分析还显示，JNK1可加重HCC的恶性程度。结果表明，GA通过靶向JNK1，可通过诱导分化和抑制干性来抑制肿瘤生长。此外，GA增强了索拉非尼在HCC治疗中的抗肿瘤作用。这些结果拓宽了我们对GA药理机制的认识以及JNK1作为HCC治疗靶点的重要性。
