title: Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor κB and miR-221.
abstract: Staphylococcal nuclease domain-containing 1 (SND1) is a multifunctional protein that is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC). Stable overexpression of SND1 in Hep3B cells expressing a low level of SND1 augments, whereas stable knockdown of SND1 in QGY-7703 cells expressing a high level of SND1 inhibits establishment of xenografts in nude mice, indicating that SND1 promotes an aggressive tumorigenic phenotype. In this study we analyzed the role of SND1 in regulating tumor angiogenesis, a hallmark of cancer. Conditioned medium from Hep3B-SND1 cells stably overexpressing SND1 augmented, whereas that from QGY-SND1si cells stably overexpressing SND1 siRNA significantly inhibited angiogenesis, as analyzed by a chicken chorioallantoic membrane assay and a human umbilical vein endothelial cell differentiation assay. We unraveled a linear pathway in which SND1-induced activation of NF-κB resulted in induction of miR-221 and subsequent induction of angiogenic factors Angiogenin and CXCL16. Inhibition of either of these components resulted in significant inhibition of SND1-induced angiogenesis, thus highlighting the importance of this molecular cascade in regulating SND1 function. Because SND1 regulates NF-κB and miR-221, two important determinants of HCC controlling the aggressive phenotype, SND1 inhibition might be an effective strategy to counteract this fatal malady.
authors.affiliation: Department of Human and Molecular Genetics, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA.
authors.forename: Prasanna Kumar
authors.initials: PK
authors.lastname: Santhekadur
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Jyoti
authors.initials: J
authors.lastname: Srivastava
authors.forename: Chadia
authors.initials: C
authors.lastname: Robertson
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000096:biosynthesis; D004720:Endonucleases; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051116:Receptors, Scavenger / Q000096:biosynthesis; D012259:Ribonuclease, Pancreatic / Q000096:biosynthesis
chemical_list: D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D004720:Endonucleases; D035683:MicroRNAs; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051116:Receptors, Scavenger; D012259:Ribonuclease, Pancreatic; C423727:CXCL16 protein, human; C525709:MIR221, human; C095221:SND1 protein, human; C046366:angiogenin