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WT1 Alternative Splicing: Role of Its Isoforms in Neuroblastoma

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Abstract

Wilms tumor 1 (WT1), a tumor suppressor gene, was originally identified in the homonymous renal neoplasm but is also involved in other cancers. Its function is still unclear, since it acts both as a pro- and an anti-oncogene. At least 14 WT1 transcriptional variants have been described; yet most investigations have focused on a small number of isoforms. We describe their structural features and review the evidence of their involvement in cancer with emphasis on neuroblastoma. In future, full characterization of all WT1 isoforms is expected to identify new molecular tumor markers and/or therapeutic targets.

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References

  • Abete I, Gómez-Úriz AM, Mansego ML, De Arce A, Goyenechea E, Blázquez V, Martínez-Zabaleta MT, González-Muniesa P, López De Munain A, Martínez JA, Campión J, Milagro FI (2015) Epigenetic changes in the methylation patterns of KCNQ1 and WT1 after a weight loss intervention program in obese stroke patients. Curr Neurovasc Res 12:321–333

    Article  CAS  PubMed  Google Scholar 

  • Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB (1993) The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40:85–97

    Article  CAS  PubMed  Google Scholar 

  • Avigad S, Feinberg-Gorenshtein G, Luria D, Jeison M, Stein J, Grunshpan A, Sverdlov Y, Ash S, Yaniv I (2009) Minimal residual disease in peripheral blood stem cell harvests from high-risk neuroblastoma patients. J Pediatr Hematol Oncol 31:22–26

    Article  PubMed  Google Scholar 

  • Bansal H, Seifert T, Bachier C, Rao M, Tomlinson G, Iyer SP, Bansal S (2012) The transcription factor Wilms tumor 1 confers resistance in myeloid leukemia cells against the proapoptotic therapeutic agent TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand) by regulating the antiapoptotic protein Bcl-xL. J Biol Chem 287:32875–32880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, Fékété CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470

    Article  CAS  PubMed  Google Scholar 

  • Bisceglia M, Vairo M, Galliani C, Lastilla G, Parafioriti A, De Maglio G, Rosai J (2011) Immunohistochemical investigation of WT1 expression in 117 embryonal tumors. Patologica 103:182–183

    Google Scholar 

  • Brocato J, Costa M (2013) Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis. Crit Rev Toxicol 43:493–514

    Article  CAS  PubMed  Google Scholar 

  • Brodeur GM, Maris JM (2006) Neuroblastoma. In: Pizzo DA, Poplack DG (eds) Principles and practice of pediatric oncology, 5th edn. Williams&Wilkins, Philadelphia, pp 933–970

    Google Scholar 

  • Bruening W, Pelletier J (1996) A non-AUG translational initiation event generates novel WT1 isoforms. J Biol Chem 271:8646–8654

    Article  CAS  PubMed  Google Scholar 

  • Bruening W, Bardeesy N, Silverman BL, Cohn RA, Machin GA, Aronson AJ, Housman D, Pelletier J (1992) Germline intronic and exonic mutations in the Wilms’ tumour gene (WT1) affecting urogenital development. Nat Genet 1:144–148

    Article  CAS  PubMed  Google Scholar 

  • Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60:509–520

    Article  CAS  PubMed  Google Scholar 

  • Caron HN, Pearson AD (2005) Neuroblastoma. In: Voute PA, Barrett A, Stevens MCG, Caron HN (eds) Cancer in children, 5th edn. Oxford University Press, Oxford, pp 337–352

    Google Scholar 

  • Carpentieri DF, Nichols K, Chou PM, Matthews M, Pawel B, Huff D (2002) The expression of WT1 in the differentiation of rhabdomyosarcoma from other pediatric small round blue cell tumors. Mod Pathol 15:1080–1086

    Article  CAS  PubMed  Google Scholar 

  • Charles AK, Mall S, Watson J, Berry PJ (1997) Expression of the Wilms’ tumour gene WT1 in the developing human and in paediatric renal tumours: an immunohistochemical study. Mol Pathol 50:138–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins CA, Guthrie C (2000) The question remains: is the spliceosome a ribozyme? Nat Struct Biol 7:850–854

    Article  CAS  PubMed  Google Scholar 

  • Cook MN, Olshan AF, Guess HA, Savitz DA, Poole C, Blatt J, Bondy ML, Pollock BH (2004) Maternal medication use and neuroblastoma in offspring. Am J Epidemiol 159:721–731

    Article  PubMed  Google Scholar 

  • Crick F (1979) Split genes and RNA splicing. Science 204:264–271

    Article  CAS  PubMed  Google Scholar 

  • D’Agata V, Cavallaro S (2004) Parkin transcript variants in rat and human brain. Neurochem Res 29:1715–1724

    Article  Google Scholar 

  • D’Agata V, Zhao W, Cavallaro S (2000) Cloning and distribution of the rat parkin mRNA. Brain Res Mol Brain Res 75:345–349

    Article  PubMed  Google Scholar 

  • Dallosso AR, Hancock AL, Brown KW, Williams AC, Jackson S, Malik K (2004) Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms’ tumours. Hum Mol Genet 13:405–415

    Article  CAS  PubMed  Google Scholar 

  • D’Amico AG, Maugeri G, Magro G, Salvatorelli L, Drago F, D’Agata V (2015) Expression pattern of parkin isoforms in lung adenocarcinomas. Tumour Biol 36:5133–5141

    Article  PubMed  CAS  Google Scholar 

  • Das R, Zhou Z, Reed R (2000) Functional association of U2 snRNP with the ATP-independent spliceosomal complex E. Mol Cell 5:779–787

    Article  CAS  PubMed  Google Scholar 

  • De Bernardi B, Pistoia V, Gambini C, Granata C (2008) Peripheral neuroblastic tumours. In: Sheaves R, Jenkins PJ, Wass JA (eds) Clinical endocrine oncology, 2nd edn. Blackwell Science, Oxford, pp 360–369

    Chapter  Google Scholar 

  • De Roos AJ, Teschke K, Savitz DA, Poole C, Grufferman S, Pollock BH, Olshan AF (2001) Parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring. Epidemiology 12:508–517

    Article  CAS  PubMed  Google Scholar 

  • Fraizer G, Leahy R, Priyadarshini S, Graham K, Delacerda J, Diaz M (2004) Suppression of prostate tumor cell growth in vivo by WT1, the Wilms’ tumor suppressor gene. Int J Oncol 24:461–471

    CAS  PubMed  Google Scholar 

  • Gatta G, Ferrari A, Stiller CA, Pastore G, Bisogno G, Trama A, Capocaccia R (2012) Embryonalcancers in Europe. Eur J Cancer 48:1425–1433

    Article  PubMed  Google Scholar 

  • Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, Dimitrova N, Jakab Z, Kaatsch P, Lacour B, Mallone S, Marcos-Gragera R, Minicozzi P, Sánchez-Pérez MJ, Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Visser O, Peris-Bonet R (2014) Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5—a population-based study. Lancet Oncol 15:35–47

    Article  PubMed  Google Scholar 

  • Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA (1990) Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778

    Article  CAS  PubMed  Google Scholar 

  • Goyal S, Mishra K, Sarkar U, Sharma S, Kumari A (2016) Diagnostic utility of Wilms’ tumour-1 protein (WT-1) immunostaining in paediatric renal tumours. Indian J Med Res 143:S59–S67

    Article  PubMed  PubMed Central  Google Scholar 

  • Guillaumet-Adkins A, Richter J, Odero MD, Sandoval J, Agirre X, Catala A, Esteller M, Prósper F, Calasanz MJ, Buño I, Kwon M, Court F, Siebert R, Monk D (2014) Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels. J Hematol Oncol 7:4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A 88:9618–9622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haber DA, Park S, Maheswaran S, Englert C, Re GG, Hazen-Martin DJ, Sens DA, Garvin AJ (1993) WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 262:2057–2059

    Article  CAS  PubMed  Google Scholar 

  • Han Y, San-Marina S, Liu J, Minden MD (2004) Transcriptional activation of c-myc proto-oncogene by WT1 protein. Oncogene 23:6933–6941

    Article  CAS  PubMed  Google Scholar 

  • Hastings ML, Krainer AR (2001) Pre-mRNA splicing in the new millennium. CurrOpin Cell Biol 13:302–309

    Article  CAS  Google Scholar 

  • Heck JE, Ritz B, Hung RJ, Hashibe M, Boffetta P (2009) The epidemiology of neuroblastoma: a review. Paediatr Perinat Epidemiol 23:125–143

    Article  PubMed  Google Scholar 

  • Hertel KJ, Graveley BR (2005) RS domains contact the pre-mRNA throughout spliceosome assembly. Trends Biochem Sci 30:115–118

    Article  CAS  PubMed  Google Scholar 

  • Hiyama E, Hiyama K, Yokoyama T, Ishii T (1991) Immunohistochemical analysis of N-myc protein expression in neuroblastoma: correlation with prognosis of patients. J Pediatr Surg 26:838–843

    Article  CAS  PubMed  Google Scholar 

  • Hohenstein P, Hastie ND (2006) The many facets of the Wilms’ tumour gene, WT1. Hum Mol Genet 15(2):R196–R201

    Article  CAS  PubMed  Google Scholar 

  • Hollander D, Naftelberg S, Lev-Maor G, Kornblihtt AR, Ast G (2016) How are short exons flanked by long introns defined and committed to splicing? Trends Genet 32:596–606

    Article  CAS  PubMed  Google Scholar 

  • Hung YP, Fletcher CD, Hornick JL (2016) Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics. Mod Pathol 29:1324–1334

    Article  CAS  PubMed  Google Scholar 

  • Jinno Y, Yun K, Nishiwaki K, Kubota T, Ogawa O, Reeve AE, Niikawa N (1994) Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat Genet 6:305–309

    Article  CAS  PubMed  Google Scholar 

  • Jurica MS, Moore MJ (2003) Pre-mRNA splicing: awash in a sea of proteins. Mol Cell 12:5–14

    Article  CAS  PubMed  Google Scholar 

  • Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M (1998) Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet 7:709–714

    Article  CAS  PubMed  Google Scholar 

  • Kletzel M, Chou PM, Olszewski M, Rademaker AW, Khan S (2015) Expression of Wilms tumor gene in high risk neuroblastoma: complementary marker to tyrosine hydroxylase for detection of minimal residual disease. Transl Pediatr 4:219–225

    PubMed  PubMed Central  Google Scholar 

  • Koesters R, Linnebacher M, Coy JF, Germann A, Schwitalle Y, Findeisen P, von KnebelDoeberitz M (2004) WT1 is a tumor-associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer 109:385–392

    Article  CAS  PubMed  Google Scholar 

  • La Cognata V, Iemmolo R, D’Agata V, Scuderi S, Drago F, Zappia M, Cavallaro S (2014) Increasing the coding potential of genomes through alternative splicing: the case of PARK2 gene. Curr Genomics 15:203–216

    Article  CAS  PubMed  Google Scholar 

  • Lee ST, Suh YL, Ko YH, Ki CS, Sung KW, Kim HJ, Kim JW, Kim SH, Chueh H, Lee SH, Yoo KH, Koo HH (2010) Measurement of tyrosine hydroxylase transcripts in bone marrow using biopsied tissue instead of aspirates for neuroblastoma. Pediatr Blood Cancer 55:273–278

    Article  PubMed  Google Scholar 

  • Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L, Weitzman SA, Korz D, Sukumar S (2001) Wilms’ tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor-specific promoter methylation. Cancer Res 61:921–925

    CAS  PubMed  Google Scholar 

  • Luksch R, Castellani MR, Collini P, De Bernardi B, Conte M, Gambini C, Gandola L, Garaventa A, Biasoni D, Podda M, Sementa AR, Gatta G, Tonini GP (2016) Neuroblastoma (peripheral neuroblastic tumours). Crit Rev Oncol Hematol 107:163–181

    Article  PubMed  Google Scholar 

  • Luna I, Such E, Cervera J, Barragán E, Ibañez M, Gómez-Seguí I, López-Pavía M, Llop M, Fuster O, Dolz S, Oltra S, Alonso C, Vera B, Lorenzo I, Martínez-Cuadrón D, Montesinos P, Senent ML, Moscardó F, Bolufer P, Sanz MA (2013) WT1 isoform expression pattern in acute myeloid leukemia. Leuk Res 37:1744–1749

    Article  CAS  PubMed  Google Scholar 

  • Magro G, Salvatorelli L, Vecchio GM, Musumeci G, Rita A, Parenti R (2014a) Cytoplasmic expression of Wilms tumor transcription factor-1 (WT1): a useful immunomarker for young-type fibromatoses and infantile fibrosarcoma. Acta Histochem 116:1134–1140

    Article  CAS  PubMed  Google Scholar 

  • Magro G, Longo F, Salvatorelli L, Vecchio GM, Parenti R (2014b) Wilms’ tumor protein (WT1) in mammary myofibroblastoma: an immunohistochemical study. Acta Histochem 116:905–910

    Article  CAS  PubMed  Google Scholar 

  • Magro G, Salvatorelli L, Puzzo L, Musumeci G, Bisceglia M, Parenti R (2015) Oncofetal expression of Wilms’ tumor 1 (WT1) protein in human fetal, adult and neoplastic skeletal muscle tissues. Acta Histochem 117:492–504

    Article  CAS  PubMed  Google Scholar 

  • Maki T, Ikeda H, Kuroda A, Kyogoku N, Yamamura Y, Tabata Y, Abiko T, Tsuchikawa T, Hida Y, Shichinohe T, Tanaka E, Kaga K, Hatanaka K, Matsuno Y, Imai N, Hirano S (2017) Differential detection of cytoplasmic Wilms tumor 1 expression by immunohistochemistry, western blotting and mRNA quantification. Int J Oncol 50:129–140

    PubMed  Google Scholar 

  • Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lacent 369:2106–2120

    CAS  Google Scholar 

  • Maroney PA, Romfo CM, Nilsen TW (2000) Functional recognition of 5′ splice site by U4/U6.U5 tri-snRNP defines a novel ATP-dependent step in early spliceosome assembly. Mol Cell 6:317–328

    Article  CAS  PubMed  Google Scholar 

  • Masserot C, Liu Q, Nguyen E, Gattolliat CH, Valteau-Couanet D, Bénard J, Huber C, Ségal-Bendirdjian E (2016) WT1 expression is inversely correlated with MYCN amplification or expression and associated with poor survival in non-MYCN-amplified neuroblastoma. Mol Oncol 10:240–252

    Article  CAS  PubMed  Google Scholar 

  • Maugeri G, D’Amico AG, Magro G, Salvatorelli L, Barbagallo GM, Saccone S, Drago F, Cavallaro S, D’Agata V (2015) Expression profile of parkin isoforms in human gliomas. Int J Oncol 47:1282–1292

    CAS  PubMed  Google Scholar 

  • Maugeri G, D’Amico AG, Rasà DM, Reitano R, Saccone S, Federico C, Parenti R, Magro G, D’Agata V (2016) Expression profile of Wilms tumor 1 (WT1) isoforms in undifferentiated and all-trans retinoic acid differentiated neuroblastoma cells. Genes Cancer 7:47–58

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mayo MW, Wang CY, Drouin SS, Madrid LV, Marshall AF, Reed JC, Weissman BE, Baldwin AS (1999) WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J 18:3990–4003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McMaster ML, Gessler M, Stanbridge EJ, Weissman BE (1995) WT1 expression alters tumorigenicity of the G401 kidney-derived cell line. Cell Growth Differ 6:1609–1617

    CAS  PubMed  Google Scholar 

  • Menke AL, Shvarts A, Riteco N, van Ham RC, van der Eb AJ, Jochemsen AG (1997) Wilms’ tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. Cancer Res 57:1353–1363

    CAS  PubMed  Google Scholar 

  • Mitsuya K, Sui H, Meguro M, Kugoh H, Jinno Y, Niikawa N, Oshimura M (1997) Paternal expression of WT1 in human fibroblasts and lymphocytes. Hum Mol Genet 6:2243–2246

    Article  CAS  PubMed  Google Scholar 

  • Moore AW, Schedl A, McInnes L, Doyle M, Hecksher-Sorensen J, Hastie ND (1998) YAC transgenic analysis reveals Wilms’ tumour 1 gene activity in the proliferating coelomic epithelium, developing diaphragm and limb. Mech Dev 79:169–184

    Article  CAS  PubMed  Google Scholar 

  • Moore AW, McInnes L, Kreidberg J, Hastie ND, Schedl A (1999) YAC complementation shows a requirement for WT1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development 126:1845–1857

    CAS  PubMed  Google Scholar 

  • Mundlos S, Pelletier J, Darveau A, Bachmann M, Winterpacht A, Zabel B (1993) Nuclear localization of the protein encoded by the Wilms’ tumor gene WT1 in embryonic and adult tissues. Development 119:1329–1341

    CAS  PubMed  Google Scholar 

  • Mžik M, Chmelařová M, John S, Laco J, Slabý O, Kiss I, Bohovicová L, Palička V, Nekvindová J (2016) Aberrant methylation of tumour suppressor genes WT1, GATA5 and PAX5 in hepatocellular carcinoma. Clin Chem Lab Med 54:1971–1980

    Article  PubMed  CAS  Google Scholar 

  • Naito H, Kuzumaki N, Uchino J, Kobayashi R, Shikano T, Ishikawa Y, Matsumoto S (1991) Detection of tyrosine hydroxylase mRNA and minimal neuroblastoma cells by the reverse transcription-polymerase chain reaction. Eur J Cancer 27:762–765

    Article  CAS  PubMed  Google Scholar 

  • Naitoh K, Kamigaki T, Matsuda E, Ibe H, Okada S, Oguma E, Kinoshita Y, Takimoto R, Makita K, Ogasawara S, Goto S (2016) Immunohistochemical analysis of WT1 antigen expression in various solid cancer cells. Anticancer Res 36:3715–3724

    PubMed  Google Scholar 

  • Nakagama H, Heinrich G, Pelletier J, Housman DE (1995) Sequence and structural requirements for high-affinity DNA binding by the WT1 gene product. Mol Cell Biol 15:1489–1498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakatsuka S, Oji Y, Horiuchi T, Kanda T, Kitagawa M, Takeuchi T, Kawano K, Kuwae Y, Yamauchi A, Okumura M, Kitamura Y, Oka Y, Kawase I, Sugiyama H, Aozasa K (2006) Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol 19:804–814

    CAS  PubMed  Google Scholar 

  • Niksic M, Slight J, Sanford JR, Caceres JF, Hastie ND (2004) The Wilms’ tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes. Hum Mol Genet 13:463–471

    Article  CAS  PubMed  Google Scholar 

  • Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S, Yao M, Takahashi E, Nakano Y, Hirabayashi H, Shintani Y, Oka Y, Tsuboi A, Hosen N, Asada M, Fujioka T, Murakami M, Kanato K, Motomura M, Kim EH, Kawakami M, Ikegame K, Ogawa H, Aozasa K, Kawase I, Sugiyama H (2002) Overexpression of the Wilms’ tumor gene WT1 in de novo lung cancers. Int J Cancer 100:297–303

    Article  CAS  PubMed  Google Scholar 

  • Oji Y, Miyoshi Y, Koga S, Nakano Y, Ando A, Nakatsuka S, Ikeba A, Takahashi E, Sakaguchi N, Yokota A, Hosen N, Ikegame K, Kawakami M, Tsuboi A, Oka Y, Ogawa H, Aozasa K, Noguchi S, Sugiyama H (2003) Overexpression of the Wilms’ tumor gene WT1 in primary thyroid cancer. Cancer Sci 94:606–611

    Article  CAS  PubMed  Google Scholar 

  • Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N, Abeno S, Ikeba A, Takashima S, Tsujie M, Yamamoto H, Sakon M, Nezu R, Kawano K, Nishida S, Ikegame K, Kawakami M, Tsuboi A, Oka Y, Yoshikawa K, Aozasa K, Monden M, Sugiyama H (2004a) Overexpression of the Wilms’ tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 95:583–587

    Article  CAS  PubMed  Google Scholar 

  • Oji Y, Miyoshi Y, Kiyotoh E, Koga S, Nakano Y, Ando A, Hosen N, Tsuboi A, Kawakami M, Ikegame K, Oka Y, Ogawa H, Noguchi S, Sugiyama H (2004b) Absence of mutations in the Wilms’ tumor gene WT1 in primary breast cancer. Jpn J Clin Oncol 34:74–77

    Article  PubMed  Google Scholar 

  • Ootsuka S, Asami S, Sasaki T, Yoshida Y, Nemoto N, Shichino H, Chin M, Mugishima H, Suzuki T (2008) Useful markers for detecting minimal residual disease in cases of neuroblastoma. Biol Pharm Bull 31:1071–1074

    Article  CAS  PubMed  Google Scholar 

  • Parareda A, Gallego S, Roma J, Llort A, Sábado C, Gros L, De Toledo JS (2005) Prognostic impact of the detection of microcirculating tumor cells by a real-time RT-PCR assay of tyrosine hydroxylase in patients with advanced neuroblastoma. Oncol Rep 14:1021–1027

    CAS  PubMed  Google Scholar 

  • Parenti R, Perris R, Vecchio GM, Salvatorelli L, Torrisi A, Gravina L, Magro G (2013) Immunohistochemical expression of Wilms’ tumor protein (WT1) in developing human epithelial and mesenchymal tissues. Acta Histochem 115:70–75

    Article  CAS  PubMed  Google Scholar 

  • Parenti R, Salvatorelli L, Musumeci G, Parenti C, Giorlandino A, Motta F, Magro G (2015) Wilms’ tumor 1 (WT1) protein expression in human developing tissues. Acta Histochem 117:386–396

    Article  CAS  PubMed  Google Scholar 

  • Patek CE, Little MH, Fleming S, Miles C, Charlieu JP, Clarke AR, Miyagawa K, Christie S, Doig J, Harrison DJ, Porteous DJ, Brookes AJ, Hooper ML, Hastie ND (1999) A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc Natl Acad Sci U S A 96:2931–2936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D (1991) Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447

    Article  CAS  PubMed  Google Scholar 

  • Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D, Van Heyningen V, Hastie N (1990) The candidate Wilms’ tumour gene is involved in genitourinary development. Nature 346:194–197

    Article  CAS  PubMed  Google Scholar 

  • Ramanathan AS, Vijayan M, Rajagopal S, Rajendiran P, Senguttuvan P (2017) WT1 and NPHS2 gene mutation analysis and clinical management of steroid-resistant nephrotic syndrome. Mol Cell Biochem 426:177–181

    Article  CAS  PubMed  Google Scholar 

  • Ramani P, Cowell JK (1996) The expression pattern of Wilms’ tumour gene (WT1) product in normal tissues and paediatric renal tumours. J Pathol 179:162–168

    Article  CAS  PubMed  Google Scholar 

  • Rauscher FJ, Morris JF, Tournay OE, Cook DM, Curran T (1990) Binding of the Wilms’ tumor locus zinc finger protein to the EGR-1 consensus sequence. Science 250:1259–1262

    Article  CAS  PubMed  Google Scholar 

  • Royer-Pokora B (2013) Genetics of pediatric renal tumors. Pediatr Nephrol 28:13–23

    Article  PubMed  Google Scholar 

  • Sahnane N, Magnoli F, Bernasconi B, Tibiletti MG, Romualdi C, Pedroni M, Ponz de Leon M, Magnani G, Reggiani-Bonetti L, Bertario L, Signoroni S, Capella C, Sessa F, Furlan D, AIFEG (2015) Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer. Clin Epigenetics 7:131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Salvatorelli L, Bisceglia M, Vecchio G, Parenti R, Galliani C, Alaggio R, Gurrera A, Giurato E, Torrisi A, Magro G (2011) A comparative immunohistochemicalstudy of oncofetal cytoplasmic WT1 expression in human fetal, adult and neoplastic skeletal muscle. Pathologica 103:186

    Google Scholar 

  • Salvatorelli L, Parenti R, Leone G, Musumeci G, Vasquez E, Magro G (2015) Wilms tumor 1 (WT1) protein: diagnostic utility in pediatrictumors. Acta Histochem 117:367–378

    Article  CAS  PubMed  Google Scholar 

  • Scharnhorst V, Dekker P, van der Eb AJ, Jochemsen AG (1999) Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties. J Biol Chem 274:23456–23462

    Article  CAS  PubMed  Google Scholar 

  • Schittenhelm J, Thiericke J, Nagel C, Meyermann R, Beschorner R (2010) WT1 expression in normal and neoplastic cranial and peripheral nerves is independent of grade of malignancy. Cancer Biomark 7:73–77

    Article  PubMed  Google Scholar 

  • Schnerwitzki D, Perner B, Hoppe B, Pietsch S, Mehringer R, Hänel F, Englert C (2014) Alternative splicing of Wilms tumor suppressor 1 (WT1) exon 4 results in protein isoforms with different functions. Dev Biol 393:24–32

    Article  CAS  PubMed  Google Scholar 

  • Schüz J, Kaletsch U, Meinert R, Kaatsch P, Spix C, Michaelis J (2001) Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany. J Clin Epidemiol 54:702–709

    Article  PubMed  Google Scholar 

  • Schwab M, Westermann F, Hero B, Berthold F (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472–480

    Article  CAS  PubMed  Google Scholar 

  • Scuderi S, La Cognata V, Drago F, Cavallaro S, D’Agata V (2014) Alternative splicing generates different parkin protein isoforms: evidences in human, rat, and mouse brain. Biomed Res Int 2014:690796

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sebire NJ, Gibson S, Rampling D, Williams S, Malone M, Ramsay AD (2005) Immunohistochemical findings in embryonal small round cell tumors with molecular diagnostic confirmation. Appl Immunohistochem Mol Morphol 13:1–5

    Article  PubMed  Google Scholar 

  • Sharma PM, Yang X, Bowman M, Roberts V, Sukumar S (1992) Molecular cloning of rat Wilms’ tumor complementary DNA and a study of messenger RNA expression in the urogenital system and the brain. Cancer Res 52:6407–6412

    CAS  PubMed  Google Scholar 

  • Sharma PM, Bowman M, Madden SL, Rauscher FJ III, Sukumar S (1994) RNA editing in the Wilms’ tumor susceptibility gene, WT1. Genes Dev 8:720–731

    Article  CAS  PubMed  Google Scholar 

  • Simpson LA, Burwell EA, Thompson KA, Shahnaz S, Chen AR, Loeb DM (2006) The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. Blood 107:4695–4702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith SI, Down M, Boyd AW, Li CL (2000) Expression of the Wilms’ tumor suppressor gene, WT1, reduces the tumorigenicity of the leukemic cell line M1 in C.B-17 scid/scid mice. Cancer Res 60:808–814

    CAS  PubMed  Google Scholar 

  • Spix C, Pastore G, Sankila R, Stiller CA, Steliarova-Foucher E (2006) Neuroblastoma incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 42:2081–2091

    Article  PubMed  Google Scholar 

  • Tadokoro K, Oki N, Fujii H, Ohshima A, Inoue T, Yamada M (1992) Genomic organization of the human WT1 gene. Jpn J Cancer Res 83:1198–1203

    Article  CAS  PubMed  Google Scholar 

  • Tatsumi N, Hojo N, Sakamoto H, Inaba R, Moriguchi N, Matsuno K, Fukuda M, Matsumura A, Hayashi S, Morimoto S, Nakata J, Fujiki F, Nishida, Nakajima H, Tsuboi A, Oka Y, Hosen N, Sugiyama H, Oji Y (2015) Identification of a novel C-terminal truncated WT1 isoform with antagonistic effects against major WT1 isoforms. PLoS One 10:e0130578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wagner KD, Wagner N, Schedl A (2003) The complex life of WT1. J Cell Sci 116:1653–1658

    Article  CAS  PubMed  Google Scholar 

  • Wang ZY, Qiu QQ, Enger KT, Deuel TF (1993) A second transcriptionally active DNA-binding site for the Wilms tumor gene product, WT1. Proc Natl Acad Sci U S A 90:8896–8900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Oue T, Uehara S, Yamanaka H, Oji Y, Fukuzawa M (2011) The role of WT1 gene in neuroblastoma. J PediatrSurg 46:326–331

    Google Scholar 

  • Yang L, Han Y, Suarez SF, Minden MD (2007) A tumor suppressor and oncogene: the WT1 story. Leukemia 21:868–876

    CAS  PubMed  Google Scholar 

  • Zitzmann F, Mayr D, Berger M, Stehr M, von Schweinitz D, Kappler R, Hubertus J (2014) Frequent hypermethylation of a CTCF binding site influences Wilms tumor 1 expression in Wilms tumors. Oncol Rep 31:1871–1876

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sections of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 87, 95123, Catania, Italy

    Daniela Maria Rasà, Agata Grazia D’Amico, Grazia Maugeri & Velia D’Agata

  2. Department of Human Science and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy

    Agata Grazia D’Amico

  3. Institute of Neurological Sciences, Italian National Research Council Catania, Catania, Italy

    Sebastiano Cavallaro

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  1. Daniela Maria Rasà
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  2. Agata Grazia D’Amico
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  3. Grazia Maugeri
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  4. Sebastiano Cavallaro
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  5. Velia D’Agata
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Correspondence to Velia D’Agata.

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Rasà, D.M., D’Amico, A.G., Maugeri, G. et al. WT1 Alternative Splicing: Role of Its Isoforms in Neuroblastoma. J Mol Neurosci 62, 131–141 (2017). https://doi.org/10.1007/s12031-017-0930-0

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  • DOI: https://doi.org/10.1007/s12031-017-0930-0

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