Wilms' Tumor Gene 1 (WT1) Silencing Inhibits Proliferation of Malignant Peripheral Nerve Sheath Tumor SNF96.2 Cell Line

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Dec 5

PMID 25474318

Citations 10

Authors

Rosalba Parenti

Venera Cardile

Adriana Carol Eleonora Graziano

Carmela Parenti

Assunta Venuti

Maria Paola Bertuccio

Debora Lo Furno

Gaetano Magro

Affiliations

Soon will be listed here.

Abstract

Wilms' tumor gene 1 (WT1) plays complex roles in tumorigenesis, acting as tumor suppressor gene or an oncogene depending on the cellular context. WT1 expression has been variably reported in both benign and malignant peripheral nerve sheath tumors (MPNSTs) by means of immunohistochemistry. The aim of the present study was to characterize its potential pathogenetic role in these relatively uncommon malignant tumors. Firstly, immunohistochemical analyses in MPNST sNF96.2 cell line showed strong WT1 staining in nuclear and perinuclear areas of neoplastic cells. Thus, we investigated the effects of silencing WT1 by RNA interference. Through Western Blot analysis and proliferation assay we found that WT1 knockdown leads to the reduction of cell growth in a time- and dose-dependent manner. siWT1 inhibited proliferation of sNF96.2 cell lines likely by influencing cell cycle progression through a decrease in the protein levels of cyclin D1 and inhibition of Akt phosphorylation compared to the control cells. These results indicate that WT1 knockdown attenuates the biological behavior of MPNST cells by decreasing Akt activity, demonstrating that WT1 is involved in the development and progression of MPNSTs. Thus, WT1 is suggested to serve as a potential therapeutic target for MPNSTs.

Citing Articles

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References

Hohenstein P, Hastie N . The many facets of the Wilms' tumour gene, WT1. Hum Mol Genet. 2006; 15 Spec No 2:R196-201. DOI: 10.1093/hmg/ddl196. View

Becanovic K, Pouladi M, Lim R, Kuhn A, Pavlidis P, Luthi-Carter R . Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis. Hum Mol Genet. 2010; 19(8):1438-52. PMC: 2846159. DOI: 10.1093/hmg/ddq018. View

Roberts S . The modulation of WTI transcription function by cofactors. Biochem Soc Symp. 2006; (73):191-201. DOI: 10.1042/bss0730191. View

Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N . Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci. 2004; 95(7):583-7. PMC: 11158491. DOI: 10.1111/j.1349-7006.2004.tb02490.x. View

Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S . Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers. Int J Cancer. 2002; 100(3):297-303. DOI: 10.1002/ijc.10476. View

Roberts S . Transcriptional regulation by WT1 in development. Curr Opin Genet Dev. 2005; 15(5):542-7. DOI: 10.1016/j.gde.2005.08.004. View

Johannessen C, Reczek E, James M, Brems H, Legius E, Cichowski K . The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005; 102(24):8573-8. PMC: 1142482. DOI: 10.1073/pnas.0503224102. View

Li Y, Rao P, Wen R, Song Y, Muir D, Wallace P . Notch and Schwann cell transformation. Oncogene. 2004; 23(5):1146-52. DOI: 10.1038/sj.onc.1207068. View

Tuna M, Chavez-Reyes A, Tari A . HER2/neu increases the expression of Wilms' Tumor 1 (WT1) protein to stimulate S-phase proliferation and inhibit apoptosis in breast cancer cells. Oncogene. 2005; 24(9):1648-52. DOI: 10.1038/sj.onc.1208345. View

10.

Katz D, Lazar A, Lev D . Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways. Expert Rev Mol Med. 2009; 11:e30. DOI: 10.1017/S1462399409001227. View

11.

Huff V . Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer. 2011; 11(2):111-21. PMC: 4332715. DOI: 10.1038/nrc3002. View

12.

Fu M, Wang C, Li Z, Sakamaki T, Pestell R . Minireview: Cyclin D1: normal and abnormal functions. Endocrinology. 2004; 145(12):5439-47. DOI: 10.1210/en.2004-0959. View

13.

Schittenhelm J, Thiericke J, Nagel C, Meyermann R, Beschorner R . WT1 expression in normal and neoplastic cranial and peripheral nerves is independent of grade of malignancy. Cancer Biomark. 2010; 7(2):73-7. DOI: 10.3233/CBM-2010-0149. View

14.

Zamora-Avila D, Franco-Molina M, Trejo-Avila L, Rodriguez-Padilla C, Resendez-Perez D, Zapata-Benavides P . RNAi silencing of the WT1 gene inhibits cell proliferation and induces apoptosis in the B16F10 murine melanoma cell line. Melanoma Res. 2007; 17(6):341-8. DOI: 10.1097/CMR.0b013e3282efd3ae. View

15.

Oue T, Uehara S, Yamanaka H, Takama Y, Oji Y, Fukuzawa M . Expression of Wilms tumor 1 gene in a variety of pediatric tumors. J Pediatr Surg. 2011; 46(12):2233-8. DOI: 10.1016/j.jpedsurg.2011.09.004. View

16.

Johansson G, Mahller Y, Collins M, Kim M, Nobukuni T, Perentesis J . Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther. 2008; 7(5):1237-45. PMC: 2855168. DOI: 10.1158/1535-7163.MCT-07-2335. View

17.

Miwa H, Beran M, Saunders G . Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia. 1992; 6(5):405-9. View

18.

Park H, Lee S, Sohn Y, Jin H, Han J, Kim Y . NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Int J Oncol. 2013; 42(2):657-66. DOI: 10.3892/ijo.2012.1751. View

19.

Loeb D, Korz D, Katsnelson M, Burwell E, Friedman A, Sukumar S . Cyclin E is a target of WT1 transcriptional repression. J Biol Chem. 2002; 277(22):19627-32. DOI: 10.1074/jbc.M201336200. View

20.

Wagner N, Wagner K, Schley G, Coupland S, Heimann H, Grantyn R . The Wilms' tumor suppressor Wt1 is associated with the differentiation of retinoblastoma cells. Cell Growth Differ. 2002; 13(7):297-305. View