title: The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma.
abstract: NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip. Robust NME1 expression was achieved following infection with the Ad5-NME1 adenovirus in the human metastasis-derived cell lines WM1158 (melanoma) and WRO82 (follicular thyroid carcinoma), resulting in wide-ranging effects on gene expression in both settings. A substantial proportion of the NME1-regulated genes identified in the analyses were of clear potential relevance to metastasis, such as matrix metalloproteinase-1 (MMP1), angiopoietin-2 (ANGPT2), SERPINB9 and colony stimulating factor receptor-2B (CSFR2B). Nine genes were identified (false discovery rate <0.1) that were regulated by NME1 in both the WM1158 and WRO82 cell lines, each possessing one or more such metastasis-relevant activities as stress fiber formation and focal adhesion (PPM1E, ZYX, PFN1), chemotaxis (CCR1) epithelial-mesenchymal signaling (WNT6), differentiation and morphogenesis (TBX4, ZFP36L2), and G protein modulation (GPR52 and PFN1). In addition, a number of the NME1-regulated genes were shown to be of prognostic value for distant disease-free survival and overall survival in melanoma and breast cancer. The combined expression of three NME1-regulated genes CSFR2B, MSF4A1 and SERPINB9 provided a strongly synergistic correlation with distant disease-free survival in the basal subtype of breast cancer (p<3.5e(-5), hazard ratio=0.33). Our study demonstrates that analysis of NME1-dependent gene expression is a powerful approach for identifying potential modulators of metastatic potential in multiple cancer types, which in turn may represent useful therapeutic targets. The study also highlights NME1-dependent genes as potential prognostic/diagnostic indices, which are profoundly lacking at present in melanoma.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, U.S.A.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: McCorkle
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD U.S.A.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Leonard
authors.affiliation: Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, U.S.A.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Kraner
authors.affiliation: Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, U.S.A.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Blalock
authors.affiliation: Department of Pathology, University of Iowa Hospitals and Clinics, University of Iowa Carver College of Medicine, Iowa City, IA, U.S.A.
authors.forename: Deqin
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, U.S.A. Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD U.S.A. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD U.S.A. Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY, U.S.A. Department of Pathology, University of Iowa Hospitals and Clinics, University of Iowa Carver College of Medicine, Iowa City, IA, U.S.A.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Zimmer
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD U.S.A. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD U.S.A. DKaetzel@som.umaryland.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D063868:Patient Outcome Assessment; D011379:Prognosis; D013964:Thyroid Neoplasms / Q000235:genetics
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; C517938:NME1 protein, human
keywords: Adenovirus; NDPK; NM23; NME1; melanoma; metastasis; metastasis suppressor; microarray; thyroid carcinoma