A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway

// Hong Zhao 1,* , Yuming Guo 2,* , Shu Li 2 , Ruiqin Han 3 , Jianming Ying 4 , Hai Zhu 2 , Yuanyuan Wang 2 , Li Yin 2 , Yuqing Han 2 , Lingzhi Sun 2 , Zhaoyi Wang 2 , Qingcong Lin 2 , Xinyu Bi 1 , Yuchen Jiao 5 , Hongying Jia 1 , Jianjun Zhao 1 , Zhen Huang 1 , Zhiyu Li 1 , Jianguo Zhou 1 , Wei Song 3 , Kun Meng 2 and Jianqiang Cai 1 1 Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 2 Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China 3 National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 4 Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 5 Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China * These authors have contributed equally to this work Correspondence to: Kun Meng, email: // JianqiangCai, email: // Keywords : Icaritin, HCC, HCC initiating cells, IL-6 receptors, Stat3 Received : May 16, 2015 Accepted : August 20, 2015 Published : September 10, 2015 Abstract Tumor-initiating cell (TIC) is a subpopulation of cells in tumors that are responsible for tumor initiation and progression. Recent studies indicate that hepatocellular carcinoma-initiating cells (HCICs) confer the high malignancy, recurrence and multi-drug resistance in hepatocellular carcinoma (HCC). In this study, we found that Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited malignant growth of HCICs. Icaritin decreased the proportion of EpCAM-positive (a HCICs marker) cells, suppressed tumorsphere formation in vitro and tumor formation in vivo . We also found that Icaritin reduced expression of Interleukin-6 Receptors (IL-6Rs), attenuated both constitutive and IL-6-induced phosphorylation of Janus-activated kinases 2 (Jak2) and Signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes, such as Bmi-1 and Oct4. The inhibitory activity of Icaritin in HCICs was augmented by siRNA-mediated silencing of Stat3 but attenuated by constitutive activation of Stat3.Taken together, our results indicate that Icaritin is able to inhibit malignant growth of HCICs and suggest that Icaritin may be developed into a novel therapeutic agent for effective treatment of HCC.