title: Hypoxia promotes HO-8910PM ovarian cancer cell invasion via Snail-mediated MT1-MMP upregulation.
abstract: The molecular mechanisms of ovarian cancer cell invasion under hypoxia remain unclear. Here we employed a 3D collagen model and chick chorioallantoic membrane (CAM) invasion assay to explore the influence of hypoxia on ovarian cancer cell invasion. Hypoxia (both 1% O2 and CoCl2 150 and 250 µM) induced HO-8910PM ovarian cancer cell invasion in 3D collagen and collagenolysis determined by hydroxyproline. Pretreatment with a hypoxia inducible factor-1α inhibitor, YC-1, or MMP inhibitor, GM6001, significantly inhibited 3D collagen invasion and degradation and cell proliferation. Hypoxia stimulated both mRNA and protein expressions of membrane-type 1 matrix metalloproteinase (MT1-MMP) and promoted MT1-MMP translocation to the cell surface in an YC-1 sensitive manner. MT1-siRNA transfection inhibited hypoxia-induced invasion, proliferation, and collagen degradation of cells in 3D collagen. Hypoxia stimulated Snail mRNA and protein expression as well as translocation to nucleus in an YC-1 sensitive manner. Overexpression of Snail with a recombinant plasmid in HO-8910PM cells resulted in an enhanced invasion in 3D collagen. Transfection with Snail-specific siRNA significantly decreased MT1-MMP expression and 3D collagen invasion. Hypoxia-treated cells significantly broke the upper CAM surface of 11-day-old chick embryos and infiltrated interstitial tissue, completely blocked in the presence of YC-1 or GM6001, or after MT1-MMP siRNA or Snail siRNA transfection. Together, these data suggest that hypoxia promotes HO-8910PM ovarian cancer cell traffic through 3D matrix via Snail-mediated MT1-MMP upregulation, a possible molecular mechanism of ovarian cancer cell invasion under hypoxia.
authors: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University,Harbin, Heilongjiang 150081, P. R. China.
authors: Lijun
authors: L
authors: Sun
authors: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors: Ping
authors: P
authors: Lin
authors: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University,Harbin, Heilongjiang 150081, P. R. China.
authors: Zhuo
authors: Z
authors: Qin
authors: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University,Harbin, Heilongjiang 150081, P. R. China.
authors: Yusi
authors: Y
authors: Liu
authors: Department of Oncology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors: Li-Li
authors: LL
authors: Deng
authors: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University,Harbin, Heilongjiang 150081, P. R. China lclian@aliyun.com.
authors: Changlian
authors: C
authors: Lu
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000737:chemistry; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D007191:Indazoles; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Hypoxia; Snail; invasion; membrane-type 1 matrix metalloproteinase; ovarian cancer; three-dimensional extracellular matrix