title: Enhanced tumorigenesis and lymphatic metastasis of CD133+ hepatocarcinoma ascites syngeneic cell lines mediated by JNK signaling pathway in vitro and in vivo.
abstract: Cancer stem cells (CSCs), stem-like cells, or tumor-initiating cells (TICs) may initiate tumorigenesis and metastasis, but neither the basic cell biology of CSCs nor the mechanisms of CSC-mediated tumor growth and lymphoid node metastasis are understood. Evidence suggests that CSC phenotype is maintained, at least in part, by altered JNK signaling. In this study, factors influencing the growth and metastatic potential of CSCs were examined by comparing CD133 surface antigen expression, proliferation, clonogenicity, invasive capacity, tumorigenicity, and expression of JNK-associated signaling molecules between the highly metastatic mouse hepatocarcinoma ascites syngeneic cell line Hca-F and the low metastasis potential line Hca-P. The Hca-F line exhibited higher clonogenic, proliferative, and invasive capacities than Hca-P cells, and a greater proportion of Hca-F cells were CD133 positive. In both cell lines, the CD133+ subpopulation showed significantly enhanced tumorigenicity and metastatic potential. An in vivo tumorigenicity assay in nude mice indicated that Hca-F cells possessed significantly higher tumorigenicity than Hca-P cells as indicated by larger tumors after inoculation. Expression levels of E-cadherin (CDH1), annexin VII, and JNK1 proteins were inversely correlated with CD133 expression in both Hca-F and Hca-P cells. These results demonstrate that CD133+ subpopulations of both Hca-F and Hca-P lines show CSC-like properties. However, Hca-F cells showed greater tumorigenicity and invasiveness, consistent with greater lymphatic metastasis capacity. We propose that tumorigenesis and lymphatic metastasis are regulated by JNK/P53/annexin VII and JNK/ATF-2/CDH1/annexin VII signal transduction pathways.
authors.affiliation: Department of Pathology, Dalian Medical University, 9 West Lvshun Southern Road, Dalian 116044, PR China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Jin
authors.forename: Jun
authors.initials: J
authors.lastname: Mao
authors.forename: Huanxi
authors.initials: H
authors.lastname: Wang
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Hou
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Huang
authors.forename: Shizhu
authors.initials: S
authors.lastname: Zang
authors.forename: Jianwu
authors.initials: J
authors.lastname: Tang
authors.forename: Lianhong
authors.initials: L
authors.lastname: Li
mesh_terms: D000071916:AC133 Antigen; D051698:Activating Transcription Factor 2 / Q000235:genetics; D000818:Animals; D017310:Annexin A7 / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D001201:Ascites / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D051698:Activating Transcription Factor 2; D017310:Annexin A7; D015703:Antigens, CD; C497106:Atf2 protein, mouse; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; C577585:Fzr1 protein, mouse; D006023:Glycoproteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D016159:Tumor Suppressor Protein p53