ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl 2 , a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxiainducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a newly discovered matrix metalloproteinase with multiple domains, including propeptide, metalloproteinase, disintegrin, and spacer region domains, and domains containing thrombospondin type I motifs (1). The ADAMTS family now contains 19 members. One of the best characterized biological functions of ADAMTS is proteolytic activity against extracellular matrix proteins, including proteoglycans (2, 3). In arthritic cartilage, aggrecan breakdown, mediated by members of ADAMTS, not matrix metalloproteinases, is one of the features of the progressive stage. ADAMTS5 (aggrecanase-2) null mice show protection against experimental arthritis (4, 5).ADAMTS1 was originally cloned from a murine colon carcinoma cell line (6). Recently, it has been reported that a polymorphism of ADAMTS1 is closely associated with the occurrence of ischemic heart disease (7). In the cardiovascular system, ADAMTS1 plays roles in atherosclerosis by degrading versican (8) and TFPI-2 (tissue factor pathway inhibitor-2) (9). We have previously reported that ADAMTS1 was induced in the infarcted heart (10); however, the regulatory mechanism of ADAMTS1 in ischemia is unknown.Low oxygen tension (hypoxia) affects endothelial cells in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins (11). One mechanism of the regulation of gene expre...

when it is degraded to lower-molecular-weight HA (LMW-HA). 3 Other biological activities of HA are also dependent on its molecular weight 4,5 : HMW-HA is anti-inflammatory and antiangiogenic, whereas LMW-HA promotes inflammatory and angiogenic reactions. 6,7 In osteoarthritis (OA), HA degradation is enhanced and so Supported by Japan Society for the Promotion of Science Grant-in-aid for Scientific Research (JSPS KAKENHI) grants 16H05454 (Y.O.), 19H03788 (Y.O.), and 18K09082 (M.I.

Our findings suggest a metastasis model proposing accumulation of a subtype of cancer cells with high metastatic capacity within heterogenous primary tumor cell population.

Materials and methods:·We performed LOR analysis in DNAs from 80 paired of normal and HNSCC tissues, by designing a microsatellit~marker on chromosome 4q35.l, which specifically detects allelic loss of ING2 locus. TP53 mutation analysis and its relationship with ING2 chromosomal deletion were also performed in available 68 of the samples. The correlation between LOR status and clinicopathological

Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAM-TS1 that occurs independent of the protease activity. (Cancer Sci 2012; 103: 1889-1897 A ngiogenesis, the formation of new blood vessels from pre-existing capillaries, is observed under various pathophysiological conditions (e.g. wound healing, diabetic retinopathy and tumor growth).(1) Neovascularization consists of endothelial cell migration, proliferation and new network formation. Tumors require a substantial blood supply, and promote angiogenesis when they grow. Avascular tumors have a severely restricted growth potential. As a result, anti-angiogenic treatments are thus considered to be potentially useful for cancer therapy.(2,3) To date, many anti-angiogenic therapies have been designed to inhibit tumor growth as well as cancer cell dissemination. (4,5) A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a newly categorized MMP, which has multiple domains, including propeptide, metalloproteinase, disintegrin-like and spacer-region domains, and domains containing thrombospondin (TSP-1) type Ι motifs.(6) ADAMTSs have diverse functions, such as pro-collagen processing (7) and cleavage of Von Willebrand factor. (8,9) One of the best characterized biological functions of ADAMTS is proteolytic activity against extracellular matrix proteins, including proteoglycans. (10)(11)(12)(13) ADAMTS1 is the first member of...