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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2015 | Research

WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1

Authors: Long Lv, Gong Chen, Jianping Zhou, Jun Li, Jianping Gong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2015

Abstract

Background

The antisense of the tumor suppressor gene WT1 (WT1-AS) is a long non-coding RNA. The role of WT1-AS in the development of hepatocellular carcinoma (HCC) has not yet been elucidated.

Methods

Quantitative real-time PCR and western blot analyses were used to measure levels of WT1-AS and its related genes in tumor and corresponding adjacent tumor tissues of HCC patients. The effect on HCC cell proliferation and apoptosis was assessed by EdU incorporation assays and PI-Annexin-V staining, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between WT1-AS and WT1 in cell lines.

Results

WT1-AS expression correlated negatively with WT1 expression in HCC tumor tissue. Kaplan-Meier curve analysis revealed that WT1-AS expression is a reliable indicator of HCC prognosis. The downregulation of WT1 expression by WT1-AS promoted cell apoptosis by suppressing the JAK/STAT3 signaling pathway. Bioinformatics analysis showed that WT1-AS downregulates WT1 by binding to the TATA region of the WT1 promotor. WT1-AS was also able to reverse WT1-mediated resistance to Dox based chemotherapy in HCC cells.

Conclusions

WT1-AS downregulates WT1 expression in HCC tumors and promotes apoptosis by binding to the promoter region of WT1. Our findings suggest that WT1-AS may function as a tumor suppressor in HCC by reversing the oncogenic effects of WT1.

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Park YY, Kim SB, Han HD, Sohn BH, Kim JH, Liang J et al. TARDBP regulates glycolysis in hepatocellular carcinomaby regulating PFKP through miR-520. Hepatology. 2013. doi:10.1002/hep.26310.

Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35(3):519–24. doi:10.1053/jhep.2002.32089.CrossRefPubMed

Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet. 1999;353(9160):1253–7. doi:10.1016/S0140-6736(98)09148-X.CrossRefPubMed

Sinha S, Thomas D, Yu L, Gentles A, Jung N, Corces-Zimmerman MR, et al. Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition. Blood. 2014. doi:10.1182/blood-2014-03-566018.

Xu W, Ji J, Xu Y, Liu Y, Shi L, Lu X et al. MicroRNA-191, by promoting the EMT and increasing CSC-like properties, is involved in neoplastic and metastatic properties of transformed human bronchial epithelial cells. Mol Carcinog. 2014. doi:10.1002/mc.22221.

Kang HJ, Park JH, Chen W, Kang SI, Moroz K, Ladanyi M, et al. EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation. Cancer Res. 2014;74(16):4526–35. doi:10.1158/0008-5472.CAN-13-3663.CrossRefPubMed

Koido S, Homma S, Okamoto M, Takakura K, Mori M, Yoshizaki S, et al. Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. Clin Cancer Res. 2014;20(16):4228–39. doi:10.1158/1078-0432.CCR-14-0314.CrossRefPubMed

Krauth MT, Alpermann T, Bacher U, Eder C, Dicker F, Ulke M, et al. WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia. 2014. doi:10.1038/leu.2014.243.

Berasain C, Herrero JI, Garcia-Trevijano ER, Avila MA, Esteban JI, Mato JM, et al. Expression of Wilms' tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Hepatology. 2003;38(1):148–57. doi:10.1053/jhep.2003.50269.CrossRefPubMed

10.

Perugorria MJ, Castillo J, Latasa MU, Goni S, Segura V, Sangro B, et al. Wilms' tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res. 2009;69(4):1358–67. doi:10.1158/0008-5472.CAN-08-2545.CrossRefPubMed

11.

Sera T, Hiasa Y, Mashiba T, Tokumoto Y, Hirooka M, Konishi I, et al. Wilms' tumour 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis. Eur J Cancer. 2008;44(4):600–8. doi:10.1016/j.ejca.2008.01.008.CrossRefPubMed

12.

Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, et al. Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2. Hepatology. 2014;60(4):1278–90. doi:10.1002/hep.27239.CrossRefPubMed

13.

He Y, Meng XM, Huang C, Wu BM, Zhang L, Lv XW, et al. Long noncoding RNAs: Novel insights into hepatocelluar carcinoma. Cancer Lett. 2014;344(1):20–7. doi:10.1016/j.canlet.2013.10.021.CrossRefPubMed

14.

Liu J, Wang DZ. An Epigenetic "LINK(RNA)" to Pathological Cardiac Hypertrophy. Cell Metab. 2014;20(4):555–7. doi:10.1016/j.cmet.2014.09.011.CrossRefPubMed

15.

Tang J, Zhuo H, Zhang X, Jiang R, Ji J, Deng L, et al. A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma. Cell Death Dis. 2014;5:e1549. doi:10.1038/cddis.2014.518.CrossRefPubMed

16.

Ni Nyoman AD, Luder CG. Apoptosis-like cell death pathways in the unicellular parasite Toxoplasma gondii following treatment with apoptosis inducers and chemotherapeutic agents: a proof-of-concept study. Apoptosis. 2013;18(6):664–80. doi:10.1007/s10495-013-0832-8.PubMedCentralCrossRefPubMed

17.

Rong Y, Cheng L, Ning H, Zou J, Zhang Y, Xu F, et al. Wilms' tumor 1 and signal transducers and activators of transcription 3 synergistically promote cell proliferation: a possible mechanism in sporadic Wilms' tumor. Cancer Res. 2006;66(16):8049–57. doi:10.1158/0008-5472.CAN-06-1172.CrossRefPubMed

18.

Li X, Li Y, Yuan T, Zhang Q, Jia Y, Li Q, et al. Exogenous expression of WT1 gene influences U937 cell biological behaviors and activates MAPK and JAK-STAT signaling pathways. Leuk Res. 2014;38(8):931–9. doi:10.1016/j.leukres.2014.05.006.CrossRefPubMed

19.

Wagner KD, Cherfils-Vicini J, Hosen N, Hohenstein P, Gilson E, Hastie ND, et al. The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression. Nat Commun. 2014;5:5852. doi:10.1038/ncomms6852.CrossRefPubMed

20.

Wang Y, Thomas A, Lau C, Rajan A, Zhu Y, Killian JK, et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Sci Rep. 2014;4:7336. doi:10.1038/srep07336.PubMedCentralCrossRefPubMed

21.

Kirschner KM, Braun JF, Jacobi CL, Rudigier LJ, Persson AB, Scholz H. Amine oxidase copper-containing 1 (AOC1) is a downstream target gene of the Wilms tumor protein, WT1, during kidney development. J Biol Chem. 2014;289(35):24452–62. doi:10.1074/jbc.M114.564336.PubMedCentralCrossRefPubMed

22.

Karki S, Surolia R, Hock TD, Guroji P, Zolak JS, Duggal R, et al. Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis. FASEB J. 2014;28(3):1122–31. doi:10.1096/fj.13-236828.PubMedCentralCrossRefPubMed

23.

Li X, Wang S, Sitaram RT, Andersson C, Ljungberg B, Li A. Single nucleotide polymorphisms in the Wilms' tumour gene 1 in clear cell renal cell carcinoma. PLoS One. 2013;8(3), e58396. doi:10.1371/journal.pone.0058396.PubMedCentralCrossRefPubMed

24.

Iiyama T, Udaka K, Takeda S, Takeuchi T, Adachi YC, Ohtsuki Y, et al. WT1 (Wilms' tumor 1) peptide immunotherapy for renal cell carcinoma. Microbiol Immunol. 2007;51(5):519–30.CrossRefPubMed

25.

Dallosso AR, Hancock AL, Malik S, Salpekar A, King-Underwood L, Pritchard-Jones K, et al. Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer. RNA. 2007;13(12):2287–99. doi:10.1261/rna.562907.PubMedCentralCrossRefPubMed

26.

Hancock AL, Brown KW, Moorwood K, Moon H, Holmgren C, Mardikar SH, et al. A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms' tumourigenesis. Hum Mol Genet. 2007;16(3):343–54. doi:10.1093/hmg/ddl478.CrossRefPubMed

Title: WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1
Authors: Long Lv
Gong Chen
Jianping Zhou
Jun Li
Jianping Gong
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2015
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-015-0233-7

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