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Integrative Genomic Analyses on Ikaros and Its Expression Related to Solid Cancer Prognosis

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Integrative Genomic Analyses on Ikaros and Its Expression Related to Solid Cancer Prognosis 571-577.qxd 24/6/2010 12:45 ÌÌ ™ÂÏ›‰·571 ONCOLOGY REPORTS 24: 571-577, 2010 571 Integrative genomic analyses on Ikaros and its expression related to solid cancer prognosis LIMING YANG1, YUMING LUO1 and JIFU WEI2 1School of Life Sciences, Huaiyin Normal University, 111 Changjiang West Road, Huai'an 223300; 2Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China Received March 10, 2010; Accepted May 3, 2010 DOI: 10.3892/or_00000894 Abstract. Ikaros is a member of the Kruppel family of zinc Introduction finger DNA-binding proteins. The Ikaros protein contains two separate regions of zinc-finger domains: 4 DNA-binding zinc The Ikaros (IKZF1, Lyf-1) is a member of the Kruppel fingers near the N-terminus and 2 zinc fingers for protein- family of zinc finger DNA-binding proteins 1 (1). The Ikaros protein interactions near the C-terminus. Here, we identified protein contains two separate regions of zinc-finger domains: the Ikaros gene from 14 vertebrate genomes and found Ikaros 4 DNA-binding zinc fingers near the N-terminus and 2 zinc existed in all kinds of vertebrate including fish, amphibians, fingers for protein-protein interactions near the C-terminus. birds and mammals. Moreover, except rat and Xenopus The human Ikaros gene, located at 7p12, contains seven exons tropicalis Ikaros proteins, which lack the first C2H2-type 1 and gives rise to at least eight isoforms by alternative splicing Zinc finger region, all identified Ikaros proteins contain six (2). All isoforms share a common C-terminal domain that C2H2-type 1 Zinc finger regions. We found human Ikaros contains a transcriptional activation domain and two zinc gene showed a predominant expression in the liver, lymph finger motifs required for hetero- or homodimerization and node, thymus, intestine, lung, mammary gland, bone marrow, for interactions with other proteins, but these isoforms differ brain, heart, placenta and prostate. Moreover, four available in the number of N-terminal zinc finger motifs. Long iso- SNPs disrupted an existing exonic splicing enhancer were forms (Ik1 to 3) have at least three zinc fingers which are identified in Ikaros. Besides the reported acute lympho- capable of binding DNA and considered to be functional. blastic leukemia (ALL), the expression of Ikaros was related Short isoforms (Ik4 to 8) lack two or more zinc-finger to the prognosis of 13 cases of cancers including blood domains, so they cannot bind DNA and impair the function cancers, breast, lung, ovarian and skin cancer. Moreover, the of Ikaros proteins in a dominant-negative manner (3-6). relationship between the expression of Ikaros and prognosis Ikaros is a transcription factor, which plays an important varied in different cancers, even in the same cancer from role in controlling hematopoietic, particularly lymphoid cell different database. Two tumor-related transcriptional factor differentiation, proliferation and function by binding upstream (c-Fos and Elk-1) binding sites were identified within the regulatory regions of target genes and aiding in their recruit- 1.5-kb regions upstream of the transcriptional start site of ment to pericentromeric heterochromatin (PC-HC) (7). This human Ikaros, which may be involved in the effect of Ikaros process leads to either activation or repression of trans- in tumors. cription of these target genes by elaborate splicing regulation of Ikaros transcripts (3-6). Accordingly, abnor- malities in splicing regulation of Ikaros would lead to _________________________________________ significant pathological manifestations (3,4,8,9). Mice that are heterozygous for a germline mutation that results in a loss of critical DNA-binding zinc fingers of Ikaros develop a very Correspondence to: Dr Liming Yang, School of Life Sciences, aggressive form of lymphoblastic leukemia, suggesting that Huaiyin Normal University, 111 Changjiang West Road, Huai'an Ikaros has an important tumor suppressor function (10,11). 223300, P.R. China Approximately 30% of pediatric B-cell acute lymphoblastic E-mail: [email protected] or leukemia (ALL) cases showed genetic inactivation of Ikaros Dr Jifu Wei, Clinical Research Center and the First Affiliated due to deletion or mutations (12-14). High-level expression Hospital of Nanjing Medical University, 300 Guangzhou Road, of dominant-negative isoforms of Ikaros with abnormal Nanjing 210029, P.R. China subcellular compartmentalization patterns were also found in E-mail: [email protected] T-cell ALL (15) and pituitary tumors (16). However, whether Ikaros is involved in other tumors formations, especially Key words: Ikaros, comparative genomics, comparative pro- solid tumors, is still unknown. teomics, cancer, prognosis, meta-analysis In the present study, we identified Ikaros genes from human, chimpanzee, macaque, orangutan, dog, cow, horse, mouse, rat, opossum, chicken, Xenopus tropicalis, zebrafish, 571-577.qxd 24/6/2010 12:45 ÌÌ ™ÂÏ›‰·572 572 YANG et al: INTEGRATIVE GENOMIC ANALYSES ON IKAROS and fugu by comparative genomic analyses. Conserved expression profiles for normal human tissues were obtained transcription factor-binding sites within promoter regions of from GeneAnnot (36) and ArrayExpress (37). Northern human Ikaros genes were then searched. The expression analysis of NCBI's uniGene dataset was also extracted data, functional relevant single nucleotide polymorphisms (34,35). (SNPs) and comparative proteomic analyses were conducted. Furthermore, meta-analysis of the prognostic value of Ikaros Meta-analysis of the prognostic value of Ikaros gene in genes in various cancers was also performed. cancer. A database named ‘PrognoScan’ has been developed (36). This is: i) a large collection of publicly available cancer Materials and methods microarray datasets with clinical annotation, as well as ii) a tool for assessing the biological relationship between gene Identification of novel Ikaros genes in vertebrate genomes expression and prognosis. PrognoScan employs the minimum and integrative genomic analyses. Ikaros genes were searched P-value approach for grouping patients for survival analysis, for in the genome sequences of human (Homo sapiens), and it provides a powerful platform for evaluating potential chimpanzee (Pan troglodytes), macaque (Macaca mulatta), tumor markers and therapeutic targets and is publicly orangutan (Pongo pygmaeus), dog (Canis familiaris), cow accessible at http://gibk21.bse.kyutech.ac.jp/PrognoScan/ (Bos taurus), horse (Equus caballus), mouse (Mus musculus), index.html. Human Ikaros (IKZF1) gene was inputted as rat (Rattus norvegicus), opossum (Monodelphis domestica), queries and the data were collected for analysis. chicken (Gallus gallus), Xenopus tropicalis, zebrafish (Danio rerio), and fugu (Takifugu rubripes) by the method described Results before using human Ikaros gene (NM_006060) as queries. The assemblies used were human NCBI 36, chimpanzee Comparative proteomics of Ikaros proteins identified in CHIMP2.1, macaque MMUL 1.0, orangutan PPYG2, vertebrate genomes. Ikaros genes were identified in the dog Canfam 2.0, cow Btau_4.0, horse Equ Cab 2, mouse genome sequences of human, chimpanzee, macaque, oran- NCBI m37, rat RGSC 3.4, opossum monDom5, chicken gutan, dog, cow, horse, mouse, rat, opossum, chicken, WASHUC2, X. tropicalis JGI 4.1, zebrafish Zv8 and fugu Xenopus tropicalis, zebrafish and fugu. Their amino acid FUGU 4.0. The identified putative Ikaros genes were sequences are shown in alignment format in Fig. 1. Except BLASTed against the database number of GenBank to rat and Xenopus tropicalis Ikaros proteins, which lack the confirm that the best hits were Ikaros genes. Conserved first C2H2-type 1 Zinc finger region, all identified Ikaros transcription factor-binding sites within promoter region of proteins containing six C2H2-type 1 Zinc finger regions human Ikaros gene were then searched for based on the Patch (Fig. 1). Refined phylogenetic trees using the identified program (http://www.gene-regulation.com) as well as manual Ikaros amino acid sequences by ML and NJ methods were inspection as previously described (17-28). almost the same (Fig. 2). It seemed that primate Ikaros proteins clustered into one group, different from other Ikaros Comparative proteomic analyses of Ikaros proteins. The amino proteins. We were unable to identify any site under positive acid sequences of Ikaros were deduced from the identified selection with any of the six models in Ikaros proteins. Ikaros genes and aligned using Clustal X 1.8 software Instead, the Ikaros proteins were under purifying selection (29). The phylogenetic tree of Ikaros was obtained by using (data not shown). ML (maximum likelihood) (PHYML v2.4.4) (30 and NJ (neighbor-joining) (MEGA 3.0) (31) methods, and the Expression profile of human Ikaros gene. By EST sequence reliability of the tree was evaluated by the bootstrap method search, human Ikaros gene was expressed in parathyroid, with 1,000 replications. The program Codeml implemented liver, lymph node, stomach, uterus, vascular, thymus, muscle, in the PAML 3.14 b software package was used to investigate pharynx, intestine, ovary, thyroid, lung, mammary gland, whether Ikaros proteins are under positive selection (32). Six blood, bone, bone marrow, brain, spleen, heart, placenta, models of codon substitution, M0 (one-ratio), M1a tonsil, prostate, and connective tissue. The investigation (NearlyNeutral), M2a (PositiveSelection), M3 (discrete), M7 of available microarray experiments and ‘virtual northern
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