title: ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma.
abstract: Frequent tumor relapse in hepatocellular carcinoma (HCC) has been commonly attributed to the presence of residual cancer stem cells (CSCs) after conventional treatments. We have previously identified and characterized CD133 to mark a specific CSC subset in HCC. In the present study, we found endogenous and secretory annexin A3 (ANXA3) to play pivotal roles in promoting cancer and stem cell-like features in CD133+ liver CSCs through a dysregulated JNK pathway. Blockade of ANXA3 with an anti-ANXA3 monoclonal antibody in vitro as well as in human HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, ANXA3 expression in HCC patient sera closely associated with aggressive clinical features. Our results suggest that ANXA3 can serve as a novel diagnostic biomarker and that the inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC.
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Man
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Tsun-Ming
authors.initials: TM
authors.lastname: Fung
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Steve T
authors.initials: ST
authors.lastname: Luk
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Ng
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Terence K
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Chi-Ho
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Judy W
authors.initials: JW
authors.lastname: Yam
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Fai
authors.initials: F
authors.lastname: Ng
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Chung-Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address: stefma@hku.hk.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
mesh_terms: D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D017318:Annexin A3 / Q000096:biosynthesis / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000235:genetics*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D017318:Annexin A3