title: Roles of HIF-1α in a novel optical orthotopic spontaneous metastatic bladder cancer animal model.
abstract: Although metastatic disease is lethal in the majority of bladder cancer cases, study on the molecular mechanism(s) of this process suffers from the limited source of distant metastatic tumor tissues and very few suitable animal models. To address this need, we generated an orthotopic animal model by instilling human bladder cancer T24-tumorigenic (T24-t) cells into mouse bladder, and sublines were subsequently derived as primary (T24-parental, T24-P) and lung metastatic (T24-L) sites. Data from invasion, migration, and adhesion assays suggested higher metastatic potential of T24-L cells than T24-P cells in vitro. Using two metastatic models to assess the metastatic ability in vivo, T24-L cells exhibited higher incidence of tumor metastasis. Mechanistically, the up-regulation of MMP-1 and HIF-1α was observed in T24-L cells. Knocking down HIF-1α can significantly down-regulate the expression of MMP-1, accompanied by the decreased invasion ability in vitro. Using immunohistochemical staining, we further observed HIF-1α elevation in the metastatic lymphomatic tissues compared with the primary bladder cancer tissues from the same patients. Taken together, our study provides the evident of the function of HIF-1α/MMP-1 in regulating metastasis of bladder cancer and HIF-1α as a potential target for controlling bladder cancer metastasis.
authors.affiliation: Department of Urology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Jinhai
authors.initials: J
authors.lastname: Fan
authors.forename: Kaijie
authors.initials: K
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Kangwei
authors.initials: K
authors.lastname: Sun
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Guan
authors.forename: Xinyang
authors.initials: X
authors.lastname: Wang
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hiesh
authors.forename: Dalin
authors.initials: D
authors.lastname: He
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020781:Matrix Metalloproteinase 1