title: AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma.
abstract: The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan-Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44-10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.
authors: Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20814, USA.
authors: Takeshi
authors: T
authors: Namiki
authors: Atsushi
authors: A
authors: Tanemura
authors: Julio C
authors: JC
authors: Valencia
authors: Sergio G
authors: SG
authors: Coelho
authors: Thierry
authors: T
authors: Passeron
authors: Masakazu
authors: M
authors: Kawaguchi
authors: Wilfred D
authors: WD
authors: Vieira
authors: Masashi
authors: M
authors: Ishikawa
authors: Wataru
authors: W
authors: Nishijima
authors: Toshiyuki
authors: T
authors: Izumo
authors: Yasuhiko
authors: Y
authors: Kaneko
authors: Ichiro
authors: I
authors: Katayama
authors: Yuji
authors: Y
authors: Yamaguchi
authors: Lanlan
authors: L
authors: Yin
authors: Eric C
authors: EC
authors: Polley
authors: Hongfang
authors: H
authors: Liu
authors: Yutaka
authors: Y
authors: Kawakami
authors: Yoshinobu
authors: Y
authors: Eishi
authors: Eishi
authors: E
authors: Takahashi
authors: Hiroo
authors: H
authors: Yokozeki
authors: Vincent J
authors: VJ
authors: Hearing
mesh_terms: D000818:Animals; D002465:Cell Movement; D016922:Cellular Senescence / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016196:S Phase / Q000235:genetics; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C546842:MTOR protein, human; C486061:NUAK2 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases