title: Angiogenin promotes tumoral growth and angiogenesis by regulating matrix metallopeptidase-2 expression via the ERK1/2 pathway.
abstract: Tumor angiogenesis is essential for tumor growth and metastasis and is dependent on key angiogenic factors. Angiogenin (ANG), a 14.2-kDa polypeptide member of the RNase A superfamily, is an angiogenic protein that has been reported to be upregulated and associated with poor prognosis in some human cancers. The mechanisms through which aberrant ANG levels promote specific steps in tumor progression are unknown. Here, we show that ANG expression in human tissues is strongly correlated with an invasive cancer phenotype. We also show that ANG induces cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth. Novel mechanistic investigations revealed that ANG expression stimulated matrix metallopeptidase-2 (MMP2) expression through the phosphorylation of ERK1/2. Targeting ANG in vivo with N65828, a small-molecule inhibitor of the ribonucleolytic activity of human ANG, resulted in the diminution of xenograft tumoral growth through the inhibition of angiogenesis. Our findings support an unrecognized interplay between ANG, ERK1/2 and MMP2 that can impact tumor growth and progression. The targeting of ANG and associated factors could provide a novel strategy to inhibit tumor establishment and growth.
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Miyake
authors.affiliation: 1] Cancer Research Institute, MD Anderson Cancer Center, Orlando, FL, USA [2] Nonagen Bioscience Corp, Orlando, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goodison
authors.affiliation: Department of Pathology, Orlando Health, Orlando, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lawton
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center, Orlando, FL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Gomes-Giacoia
authors.affiliation: 1] Cancer Research Institute, MD Anderson Cancer Center, Orlando, FL, USA [2] Nonagen Bioscience Corp, Orlando, FL, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rosser
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2