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 relapsefree 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.sucrose nonfermenting-like kinase | chromosome 1q T he identification of genes that participate in melanomagenesis should suggest strategies for developing effective therapeutic modalities (1, 2). For more than three decades, cytogenetic analyses have been used to identify genes that have an impact on tumorigenesis (3). However, those cytogenetic analyses have had limited success in elucidating such genes in solid tumors such as malignant melanoma because of the complexity of chromosomal and genomic aberrations (4, 5). Recent advances in microarray technologies, including array-based comparative genomic hybridization (CGH), have allowed the genomic characterization of cancer cells in solid tumors (6-10). Gains of chromosome 1q are frequent events in many types of cancers, including breast cancer, medulloblastoma, retinoblastoma, hepatocellular carcinoma, nonsmall cell lung carcinoma, cervical cancer, and others (11-16). Cytogenetic studies have revealed that melanoma cells have several characteristic abnormalities including a recurring translocation involving chromosomes 1 and 6 that results in gains of chromosome 1q (17,18). We previously reported a CGH analysis which showed that gains of chromosomes 1q and 6p correlate strongly with the clinical outcome of patients with primary cutaneous melanomas (19).NUAK2 ...

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

“…Strikingly, the exact same GO terms were enriched for miR-143, GO:0042981 'regulation of apoptosis' (Benjamini-Hochberg P = 0.049), GO:0043067 'regulation of programmed cell death' (BenjaminiHochberg P = 0.033) and GO:0010941 'regulation of cell death' (Benjamini-Hochberg P = 0.025). Target genes encompassed by these GO terms for both miRNAs included those normally upregulated in oncogenesis, such as NUAK2 (Namiki et al 2011), EGFR (copy number gain seen in 4% SBNETs (Banck et al 2013)), KRAS, NRAS, IGF1 , Reidy-Lagunes et al 2012, MAPK1 (ERK1) , BCL2, ARHGEF7 and BMP7 (Supplementary Table 4). Target genes specific only for miR-1 included HGF (Svejda et al 2013) and VEGFA.…”

SNF1/AMP-Activated Protein Kinases: Genes, Expression and Biological Role

“…Moreover, the incidence of both adenomas and aberrant crypt foci were significantly higher in SNARK(+/-) mice than in their wild-type counterparts, suggesting that SNARK deficiency contributed to the early phase of tumourigenesis via obesity-dependent and obesity-independent mechanisms [14]. Recently, Namiki et al [14] have shown that AMP kinase-related kinase SNARK affects tumour growth, migration, and clinical outcome of human melanoma, further supporting the importance of this protein kinase in cancer development and tumour progression, while AMPK has antioncogenic properties. We have also shown that the SNF1/AMP-activated protein kinase-related kinase is a sensitive marker for the action of ecotoxicant methyl tert-butyl ether (MTBE) as well as silver nanoparticles [15,16].…”

“…This activity is believed to be due to their activation by various forms of metabolic stress such as glucose deprivation, a condition to be expected within solid tumours [28]. Recently, Namiki et al [14] showed that AMP kinase-related kinase NUAK2 affects tumour growth, migration, and clinical outcome of human melanoma. This study further supports the importance of NUAK2 in cancer development and tumour progression, while AMPK has antioncogenic properties.…”

“…High expression level and phosphorylation status of PFKFB-3 as an important glycolytic regulator was determined in different malignant tumours [43][44][45][46][47]. Because SNARK deficiency contributed to the early phase of tumourigenesis and is important in cancer development and tumour progression [13,14], investigation of the expression of PFKFB-3 and its alternative splice variants, which have different proliferative properties [48], is necessary for understanding the role of SNARK deficiency in tumourigenesis.…”

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

“…1). In terms of human disease, NUAK2 was shown to contribute to the development of melanomas (Namiki et al, 2011). Other roles for NUAK2 were identified in heterozygous NUAK2 mice, which display mature-onset obesity and related metabolic disorders and also have a higher risk of developing colorectal cancers.…”