title: A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma.
abstract: Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Zhangang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Chi Han
authors.initials: CH
authors.lastname: Li
authors.affiliation: Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Feiyue
authors.initials: F
authors.lastname: Xu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Lu
authors.initials: L
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. frankch@cuhk.edu.hk chkcheng@cuhk.edu.hk.
authors.forename: Christopher H K
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. frankch@cuhk.edu.hk chkcheng@cuhk.edu.hk.
authors.forename: Yangchao
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000008:administration & dosage*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D054852:Small Molecule Libraries / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C000594178:2'-hydroxy-2,4,4',5,6'-pentamethylchalcone; D000970:Antineoplastic Agents; D047188:Chalcones; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1