title: Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells.
abstract: Cancer stem-like cells/cancer-initiating cells (CSCs/CICs) are considered to represent a small population of cancer cells that is resistant to conventional cancer treatments and responsible for tumor recurrence and metastasis. The aim of this study was to establish CSC/CIC-targeting immunotherapy. In this study, we found that Annexin A3 (ANXA3) was preferentially expressed in CSCs/CICs derived from hepatocellular carcinoma (HCC) cells compared to non-CSCs/CICs. In HCC samples, high levels of ANXA3 correlated with expansion of CD133(+) tumor cells representing CSCs/CICs in HCC; the combination of high levels of ANXA3 and CD133 was associated with progression of HCC. Overexpression of ANXA3 increased the proportion of CD133(+) cells, enhancing their tumorigenicity. On the contrary, knockdown of ANXA3 decreased CD133(+) cells and inhibited tumorigenicity. The mechanistic study revealed that ANXA3-mediated maintenance of HCC CSCs/CICs activity was likely involved with the HIF1A/Notch pathway. Using ANXA3 as a target, ANXA3-transfected dendritic cells could induce more functionally active T cells and these effector T cells could superiorly kill CD133(+) HCC CSCs/CICs in vitro and in vivo. Taken together, our findings suggest that ANXA3 plays a role in HCC CSC/CIC maintenance, and that ANXA3 may represent a potential CSC/CIC-specific therapeutic target for improving the treatment of HCC.
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China; Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
authors.forename: Qiu-Zhong
authors.initials: QZ
authors.lastname: Pan
authors.forename: Ke
authors.initials: K
authors.lastname: Pan
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Wang
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Weng
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Zheng
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Jiang
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Chang-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Zhang
authors.forename: Jian-Chuan
authors.initials: JC
authors.lastname: Xia
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D017318:Annexin A3 / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014162:Transfection
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D051880:Receptors, Notch; D017318:Annexin A3
keywords: ANXA3; Cancer immunotherapy; Cancer stem-like cell; Cytotoxic T lymphocytes; Hepatocellular carcinoma