title: A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway.
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.
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ruiqin
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Han
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Sun
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Zhaoyi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Qingcong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bi
authors.affiliation: 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.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Beijing Shenogen Biomedical Co., Ltd, Beijing, P.R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Meng
authors.affiliation: Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Cai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2; C499403:icaritin
keywords: HCC; HCC initiating cells; IL-6 receptors; Icaritin; Stat3