title: Up-regulation of tissue inhibitor of metalloproteinase-2 promotes SHI-1 cell invasion in nude mice.
abstract: The role of tissue inhibitor of metalloproteinase-2 (TIMP-2) in extramedullary infiltration of acute leukemia is unclear. We demonstrated in our previous study that the up-regulation of TIMP-2 promoted SHI-1 cell invasion in vitro. We investigated in the present study whether TIMP-2 would have the same effect in vivo. A retroviral vector carrying human TIMP-2 cDNA was constructed and transfected into SHI-1 cells. Three subclone cells (S1, S2 and S3) that highly expressed TIMP-2 were selected to establish nude mouse models of acute leukemia. Times of leukemic onset in mice of S1, S2 and S3 groups were all earlier than that of the SHI-1 group, whereas the survival times of S1, S2 and S3 groups were all shorter than that of the SHI-1 group (p < 0.05). Histopathological results demonstrated severe leukemic infiltration in numerous organs in each group. Reverse transcription polymerase chain reaction (RT-PCR) assay showed that several organs expressed the MLL/F6 fusion gene. Moreover, the numbers of organs infiltrated by leukemic cells in S1, S2 and S3 groups were more than those in the SHI-1 group (p < 0.05). Up-regulating TIMP-2 expression enhanced SHI-1 cell invasion in nude mice and resulted in more severe leukemia infiltration. This phenomenon suggests that targeted therapy with TIMP-2 for acute leukemia should be performed with prudence.
authors.affiliation: Department of Hematology and Oncology, Zhongda Hospital, Medical School of Southeast University , Nanjing , China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Wang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Cai
authors.forename: Baoan
authors.initials: B
authors.lastname: Chen
authors.forename: Zhengmei
authors.initials: Z
authors.lastname: He
authors.forename: Zixing
authors.initials: Z
authors.lastname: Chen
authors.forename: Jiannong
authors.initials: J
authors.lastname: Cen
authors.forename: Zhenjiang
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017254:Leukemic Infiltration; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C447400:MLL-AF6 fusion protein, human; D015514:Oncogene Proteins, Fusion; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D051788:Myeloid-Lymphoid Leukemia Protein; D017493:Leukocyte Common Antigens