title: Inactivation of von Hippel-Lindau increases ovarian cancer cell aggressiveness through the HIF1α/miR-210/VMP1 signaling pathway.
abstract: The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene not only results in tumor initiation, but also mediates tumor metastasis. However, the mechanisms by which VHL inactivation leads to metastasis have not yet been well defined. In this study, the silencing of VHL in 3AO and SKOV3 ovarian cancer cells was found to promote cell motility and to increase the expression of matrix metalloproteinase (MMP)2, MMP9, hypoxia-inducible factor 1-α (HIF-1α) and microRNA (miR)-210. The suppression of HIF-1α with its inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) in VHL-silenced 3AO cells antagonized the pro-migratory activity induced by the VHL deficiency and reversed the upregulation of MMP2, MMP9, HIF-1α and miR-210; however, it had no obvious effect on the VHL protein level. The introduction of miR-210 inhibitor into VHL-silenced 3AO cells resulted in similar changes as those induced by YC-1. Furthermore, vacuole membrane protein 1 (VMP1) was found to be diminished by VHL silencing in a HIF-1α/miR-210-dependent manner. Taken together, our data demonstrate that the loss of VHL stimulates ovarian cancer cell migration by stabilizing HIF-1α, upregulating miR-210 and decreasing VMP1 expression. These results indicate that the aberrant signaling of the VHL/HIF-1α/miR-210/VMP1 pathway may be involved in ovarian cancer aggressiveness.
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Center for Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Huilian
authors.initials: H
authors.lastname: Hou
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ding
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9