Identifying the role of Wilms tumor 1 associated protein in cancer prediction using integrative genomic analyses
- Authors:
- Published online on: July 18, 2016 https://doi.org/10.3892/mmr.2016.5528
- Pages: 2823-2831
Abstract
Introduction
The Wilms tumor suppressor gene WT1 was first identified due to its essential role in the normal development of the human genitourinary system (1). WT1 functions as a transcription factor regulating target gene expression (1). In addition, WT1 was revealed to regulate the expression of genes involved in the Wnt signaling pathway via a genome-wide screening analysis (2).
Wilms tumor 1 associated protein (WTAP) was demonstrated to interact with WT1 using a yeast two-hybrid screening (3). WTAP and WT1 were observed to localize to the nucleoplasm and nuclear speckles, where they were partially co-localized with splicing factors (3). WTAP is the mammalian homolog of the Drosophila gene female-lethal(2) D [fl(2)D], and fl(2)D is involved in activating female-specific patterns of alternative splicing of sex-lethal and transformer pre-mRNA (4,5). Previous studies demonstrated that WTAP-null and heterozygous mice succumbed between embryonic day 6.5 and 10.5, and exhibited marked defects in cell proliferation, which resulted in defects in endoderm and mesoderm formation (6,7). Furthermore, it has been demonstrated in mice that WTAP is required for G2/M cell cycle transition by stabilizing the cyclin A2 mRNA and, thus, is vital in early development (6). In addition, WTAP is involved in the function of human spliceosomes (8). Recently, it was demonstrated that WTAP and virilizer are subunits of the N6-methyladenosine methylation complex, which regulates mRNA stability (9,10).
A limited number of studies have been performed on the role of WTAP in tumor genesis. WTAP is overexpressed in cholangiocarcinoma and WTAP expression was observed to correlate with metastasis (11). In addition, WTAP was demonstrated to be overexpressed in glioblastoma, and regulated glioblastoma cell migration and invasion (12). Bansal et al (13) identified WTAP as an oncogenic protein in acute myeloid leukemia. Carbonic anhydrase 4, a novel tumor suppressor in colorectal cancer, inhibited the Wnt signaling pathway by targeting the WTAP-WT1-transducin β-like 1 axis (14). The aim of the present study was to investigate the role of WTAP in tumor formation by identifying novel WTAP genes in vertebrate genomes. The expression of these genes in healthy and tumor tissue samples was determined, and functionally relevant single nucleotide polymorphisms (SNPs) and somatic mutations in WTAP were identified. Conserved transcription factor binding sites within the promoter region of the human WTAP gene were identified. Furthermore, meta-analysis of the prognostic value of WTAP gene expression in various cancers was performed.
Materials and methods
Identification of novel WTAP genes in vertebrate genomes and transcription factor-binding sites
The DNA and amino acid sequences of novel vertebrate WTAPs were obtained by searching Ensembl genome databases (ensembl.org/index.html) using orthologous and paralogous associations. The prospective WTAP sequences were confirmed using the Basic Local Alignment Search Tool (BLAST; http://blast.ncbi.nlm.nih.gov/Blast.cgi) (15–18). Conserved transcription factor-binding sites in the promoter regions of the human WTAP gene were identified from the SABiosciences' proprietary database, DECODE (Qiagen, Inc., Valencia, CA, USA), which combines text mining with the University of California, Santa Cruz genome browser data (19–21).
Comparative proteomic analyses of WTAP proteins
The amino acid sequences of identified vertebrate WTAPs were aligned using ClustalW (ebi.ac.uk/Tools/msa/). A maximum likelihood (ML) tree of vertebrate WTAPs was constructed using Molecular Evolutionary Genetics Analysis version 5.05 (megasoftware.net/) with the optimal model (Kimura 2-parameter model). The relative support of internal nodes was determined by bootstrap analyses with 1,000 replications for ML reconstructions (22). The program, codeml within the Phylogenetic Analysis by ML version 4.7 software package (abacus.gene.ucl.ac.uk/software/paml.html) was used to investigate whether WTAP proteins were positively selected (23).
Identification of functionally relevant SNPs in the human WTAP gene and somatic mutations in human cancer
The functionally relevant SNPs of the human WTAP gene were extracted from the Ensembl genome databases and the Short Genetic Variations database (ncbi.nlm.nih.gov/snp), as previously described (15–21). The SNPs causing missense mutations were then identified. The somatic mutations of the human WTAP gene in cancer tissues were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database (cancer.sanger.ac.uk/cosmic), which mines somatic mutations in complete cancer genomes (24).
In silico expression analyses of the human WTAP gene
Expression profiles of the human WTAP gene in normal tissues were obtained from the GeneAnnot (genecards.weizmann.ac.il/geneannot/index.shtml) (25) and ArrayExpress (ebi.ac.uk/arrayexpress/) databases (26).
Meta-analysis of the prognostic value of human WTAP gene expression in cancer tissues
The expression of the WTAP gene and the biological association between gene expression and prognosis were determined by inputting human WTAP gene (NP_001257460) into the PrognoScan database (prognoscan.org/) (27).
Results
Comparative proteomics of WTAP proteins identified in vertebrate genomes
WTAP DNA and protein sequences were collected from the Ensembl genome database and confirmed by BLASTing. Completed WTAP genes were identified in the following genomes: Human, chimpanzee, gibbon, macaque, gorilla, orangutan, olive baboon, vervet monkey, marmoset, tarsier, bush baby, armadillo, sloth, squirrel, elephant, guinea pig, mouse, rat, pika, horse, microbat, ferret, dolphin, dog, pig, sheep, cow, alpaca, chicken, duck, turkey, flycatcher, zebra finch, Chinese softshell turtle, anole lizard, spotted gar, Amazon molly, platyfish, stickleback, tilapia, medaka, cave fish and zebrafish. In the armadillo genome, two WTAP genes were identified. The maximum likelihood method was used to construct the phylogenetic tree of vertebrate WTAPs (Fig. 1). The vertebrate WTAP genes clustered into the primate, rodent and teleost lineages. Furthermore, site-specific analysis for positive selection with six models of codon substitution, M0 (one-ratio), M1a (nearly neutral), M2a (positive selection), M3 (discrete), M7 (β), and M8 (β and ω) were performed in vertebrate, mammalian, bird, reptile and teleost lineages. No sites were identified under positive selection with any models in the various WTAP groups. Therefore, it was concluded that WTAP proteins were under purifying selection (data not shown).
Expression profile of the human WTAP gene
Investigation of available microarray data revealed that the human WTAP gene was predominantly expressed in the following tissues: Bone marrow, whole blood, lymph node, brain, cerebellum, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocyte, kidney, liver, lung, pancreas, thyroid, salivary gland, adrenal gland, skin, ovary, uterus, placenta, prostate and testis. In addition, the human WTAP gene was expressed in the following types of cancer: Bladder, blood, brain, breast, colorectal, esophagus, eye, head and neck, lung, ovarian, prostate, skin and soft tissue.
Comparative genomics on the human WTAP gene
Signal transducer and activator of transcription 1 (STAT1), forkhead box protein O1 (FOXO1), interferon regulatory factor 1 (IRF1), glucocorticoid receptor and peroxisome proliferator-activated receptor γ (PPARγ) transcription factor binding sites were identified in the upstream (promoter) region of the WTAP gene.
Functionally relevant SNP identification in the human WTAP gene
A total of 1,347 available SNPs were identified in the human WTAP gene. Among these, 19 SNPs were functionally relevant, causing missense mutations (Table I).
Identification of somatic mutations of the WTAP gene in human cancer
By searching the COSMIC database, 65 somatic mutations of the human WTAP gene were identified in various types of cancer tissue (Table II).
Meta-analysis of the prognostic value of human WTAP gene expression in cancer tissues
A total of 17 out of 328 microarrays identified an association between WTAP gene expressions and cancer prognosis (bladder cancers, 1/7; blood cancers, 0/37; brain cancers, 1/23; breast cancers, 5/110; colorectal cancers, 3/48; esophagus cancers, 0/1; eye cancers, 2/5; head and neck cancers, 0/6; lung cancers, 4/56; ovarian cancers, 0/25; prostate cancers, 0/1; skin cancers, 0/6; and soft tissue cancers, 1/3), P<0.05 (Table III) (28–38). In bladder, brain, eye and soft tissue cancers, reduced expression of the WTAP gene was associated with poor survival. However, an increased expression of the WTAP gene was associated with poor survival in lung cancer. Of the six breast cancer microarrays, reduced expression of the WTAP gene was associated with poor survival in two cases from the same database (GSE2990) and in the database GSE1456-GPL96, while increased expression of the WTAP gene was associated with poor survival in the GSE1456-GPL96 and GSE1456-GPL97 databases. Of the colorectal cancer microarrays, reduced expression of the WTAP gene was associated with poor survival in two cases (GSE17537 and GSE17538), while increased expression of the WTAP gene was associated with poor survival in the GSE14333 database.
Discussion
WT1 was first identified due to its essential role in the normal development of the human genitourinary system (1) and WTAP was identified as a protein that interacted with WT1 (3). A total of 44 complete WTAP genes were identified in the human, chimpanzee, gibbon, macaque, gorilla, orangutan, olive baboon, vervet monkey, marmoset, tarsier, bush baby, armadillo, sloth, squirrel, elephant, guinea pig, mouse, rat, pika, horse, microbat, ferret, dolphin, dog, pig, sheep, cow, alpaca, chicken, duck, turkey, flycatcher, zebra finch, Chinese softshell turtle, anole lizard, spotted gar, Amazon molly, platyfish, stickleback, tilapia, medaka, cave fish and zebrafish genomes. It was observed that WTAP genes were widely expressed in vertebrates, existing in fish, amphibians, birds and mammals. The phylogenetic tree revealed that the vertebrate WTAP proteins were clustered into the primate, rodent and teleost lineages. All vertebrate WTAPs are conserved according to the analysis of alignment and phylogenetic tree construction. Furthermore, the vertebrate WTAPs were under purifying selection. These results suggest that WTAP performs an essential physiological role in all vertebrates.
WTAP was predominantly expressed in bone marrow, whole blood, lymph node, brain, cerebellum, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocyte, kidney, liver, lung, pancreas, thyroid, salivary gland, adrenal gland, skin, ovary, uterus, placenta, prostate and testis. The expression pattern of WTAP appeared to be ubiquitous, which is indicative of a housekeeping role. By contrast, WT1 is expressed at low levels in only the spleen, heart, gonad and kidney (3). A total of 19 SNPs that cause missense mutations were identified in the human WTAP gene; however, it remains unclear whether these SNPs affect the physiological or pathological functions of WTAP.
WTAP and WT1 partially co-localize with splicing factors, and are distributed together in the nucleoplasm and in nuclear speckles (3). It has been demonstrated in numerous tumors that WT1 is a tumor suppressor, exerting effects including inhibiting cell proliferation and enhancing apoptosis (39–42). However, WTAP is an oncogene, which is overexpressed in cholangiocarcinoma (11), glioblastoma (12) and acute myeloid leukemia (13). In the present study, it was demonstrated that WTAP was expressed in bladder, blood, brain, breast, colorectal, esophagus, eye, head and neck, lung, ovarian, prostate, skin and soft tissue cancers. Of a total of 328 microarrays, 17 revealed an association between microarray WTAP expression and cancer prognosis (bladder cancers, 1; brain cancers, 1; breast cancers, 6; colorectal cancers, 3; eye cancers, 2; lung cancers, 4; and soft tissue cancers, 1). The majority of microarrays did not reveal an association between microarray WTAP expression and cancer prognosis. This may be due to a lack of WTAP expression information in the database. Notably, WTAP was not involved in all tumor types. In addition, it is notable that the association between WTAP expression and prognosis varied between the different cancer types, and even in identical cancers from separate databases. This suggests that the function of WTAP in these tumors may not be solely as an oncogene, but may be multidimensional (11–13). The differing WTAP expression in various tumors may be due to the distinct oncogenes or tumor suppressors stabilized by WTAP in particular tumors (9,10).
Furthermore, 65 somatic mutations of WTAP were identified in cancer tissues. The effects of these mutations on tumor formation remain to be elucidated and require future investigation. The results of the present study suggest that WTAP has a comprehensive and complex role in tumor formation. STAT1, FOXO1, IRF1, glucocorticoid receptor and PPARγ transcription factor binding sites were identified in the upstream (promoter) region of the WTAP gene. STAT1 is a cytoplasmic protein, which functions as a signal messenger and transcription factor in cellular responses to cytokines and growth factors (43). It exhibits anti-tumor functions via control of the immune system and promotion of tumor immune surveillance (44–46). FOXO1 is an important transcriptional regulator of cell proliferation and is considered to be essential for tumor growth and progression (47). Deregulation of FOXO1 promotes cell proliferation and tumorigenesis, and has thus become a primary target of tumorigenesis prevention (48,49). IRF1 is involved in the regulation of interferon α and β transcription, and it has been demonstrated that IRF1 gene deletion or rearrangement correlates with the development of human cancers (50,51). The glucocorticoid receptor is a member of the nuclear receptor family, which acts as a ligand-dependent transcription factor to regulate gene expression. In addition, the estrogen and androgen receptors are members of the nuclear receptor family. In breast cancer, the estrogen receptor drives cell growth, proliferation and metastasis, and the androgen receptor has a similar role in prostate cancer (52,53). These tumor-associated transcriptional factors may affect the expression of WTAP and contribute to tumor formation (12–14).
In conclusion, 44 complete WTAP genes were identified in vertebrate genomes. The vertebrate WTAP proteins clustered into the primate, rodent and teleost lineages. The association between WTAP gene expression and prognosis varied in distinct cancers, and even in identical cancers from separate microarray databases. Furthermore, a total of 65 somatic mutations were identified in the human WTAP gene from cancer tissue samples. The results of the present study suggest that the function of WTAP in tumor formation may be multidimensional.
Acknowledgments
The present study was supported by Anhui Science and Technology Research Projects (grant no. 130zc04065), the National Natural Science Foundation of China (grant nos. 81372828 and 810001329), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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