Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types
- 342 Downloads
Non-metastatic 23 [NM23/nucleoside diphosphate kinases (NDPK)] genes are the first discovered metastasis suppressor genes. More than two decades of research has demonstrated their roles in a variety of biological processes with NME1 and NME2 being most studied in the context of metastasis suppression. Although NME1 and NME2 share >85% homology at amino acid level, they show redundant as well as unique molecular functions. Phenotypic analyses of knockout (KO) mice for NM23 members (NDPK-A, B) and compound KO (A as well as B) showed requirement of both proteins in hematopoiesis suggesting shared functions in development disease. Several reviews have discussed NME1, however the role of NME2 appears to be relatively less understood in the context of metastasis suppression. Here, we focus on NME2 and by meta-analysis of gene expression from multiple tumor types, and survey of in vivo and vitro studies, suggest the possibility that NME2 may be one of the key factors in metastasis. This along with the relevance of normal physiological functions of NME2 in the context of metastasis is discussed. We further examined the genetic and epigenetic features of NME2 and NME1 gene promoters and found aspects of transcription control that could be unique to NME2/NME1. Findings on signaling pathways and small molecules which regulate the expression of NME2 that could be therapeutically important are also discussed.
KeywordsNM23 Meta-analysis Metastasis Transcription Metastasis suppression Regulation NME2 promoter NM23 H2
We thank all members of SC lab for helpful discussion. Research grant from CSIR (MLP 5501), DST (Swarnajayanti Fellowship to SC), and Senior Research Fellowship to VKY (CSIR) and PK (ICMR) is acknowledged. Gene expression datasets from multiple tumor types for analysis of NME2 transcript level were obtained from expO (IGC, USA, www.intgen.org). Datasets for ChIP-seq analysis were from ENCODE consortium (http://genome.ucsc.edu/ENCODE/downloads.html).
Conflicts of interest
- Bhujwalla ZM, Aboagye EO, Gillies RJ, Chacko VP, Mendola CE, Backer JM (1999) Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med 41:897–903PubMedCrossRefGoogle Scholar
- Fournier HN, Dupe-Manet S, Bouvard D, Lacombe ML, Marie C, Block MR, biges-Rizo C (2002) Integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha ) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. J Biol Chem 277:20895–20902PubMedCrossRefGoogle Scholar
- Fukuda M, Ishii A, Yasutomo Y, Shimada N, Ishikawa N, Hanai N, Nagata N, Irimura T, Nicolson GL, Kimura N (1996) Decreased expression of nucleoside diphosphate kinase alpha isoform, an nm23-H2 gene homolog, is associated with metastatic potential of rat mammary-adenocarcinoma cells. Int J Cancer 65:531–537PubMedCrossRefGoogle Scholar
- Herak BM, Bago R, Konjevoda P, Pavelic J (2008) Gene expression profiling of Nm23-H2 overexpressing CAL 27 cells using DNA microarray. Neoplasma 55:447–454Google Scholar
- Joosten M, Blazquez-Domingo M, Lindeboom F, Boulme F, Van Hoven-Beijen A, Habermann B, Lowenberg B, Beug H, Mullner EW, Delwel R, Von LM (2004) Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling. J Biol Chem 279:38169–38176PubMedCrossRefGoogle Scholar
- Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV, Kloos DU, Land S, Lewicki-Potapov B, Michael H, Munch R, Reuter I, Rotert S, Saxel H, Scheer M, Thiele S, Wingender E (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31:374–378PubMedCrossRefGoogle Scholar
- Miyazaki H, Fukuda M, Ishijima Y, Takagi Y, Iimura T, Negishi A, Hirayama R, Ishikawa N, Amagasa T, Kimura N (1999) Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res 5:4301–4307PubMedGoogle Scholar
- Srivastava S, Li Z, Ko K, Choudhury P, Albaqumi M, Johnson AK, Yan Y, Backer JM, Unutmaz D, Coetzee WA, Skolnik EY (2006) Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol Cell 24:665–675PubMedCrossRefGoogle Scholar