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Wilms tumor-suppressing peptide inhibits proliferation and induces apoptosis of Wilms tumor cells in vitro and in vivo

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Our previous study identified a Wilms tumor-suppressing peptide (WTSP) that was upregulated in healthy children, but downregulated in children with Wilms tumor (WT). This study aimed to investigate the effect of WTSP on WT growth in vivo and in vitro.

Methods

WTSP was synthesized by solid-phase synthesis of FOMC-protected amino acids. Cell growth curve, cytotoxicity, and apoptosis of WTSP-treated human WT cell line (SK-NEP-1) were determined by cell count, Cell Counting Kit-8 assay, and flow cytometry. The expression of key proteins of four WT-associated signaling pathways was determined by real-time PCR and western blotting. The WT xenograft mouse model was established by the armpit injection of SK-NEP-1 cells. The TUNEL assay was used to detect apoptosis in mouse tumor cells.

Results

WTSP inhibited the proliferation of SK-NEP-1 cells in a dose- and time-dependent manner, and it arrested SK-NEP-1 cells in G2/M phase. WTSP-treated cells exhibited a low expression of PCNA and Bcl-2 and high expression of Bax. The expression of β-catenin was markedly changed after WTSP treatment. WTSP-treated mice had significantly smaller tumors than untreated mice.

Conclusion

Our findings indicated an anti-tumor effect of WTSP, which is correlated with Wnt/β-catenin pathway. This newly identified peptide may exert a therapeutic effect of WT in the future.

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References

  • Akyüz C, Yalçin B, Yildiz I et al (2010) Treatment of Wilms tumor: a report from the Turkish Pediatric Oncology Group (TPOG). J Pediatr Urol 6(3):S59–S60

    Article  Google Scholar 

  • Amarante MK, de Oliveira CEC, Ariza CB, Sakaguchi AY, Ishibashi CM, Watanabe MAE (2017) The predictive value of transforming growth factor-β in Wilms tumor immunopathogenesis. Int Rev Immunol 36(4):233–239

    Article  CAS  PubMed  Google Scholar 

  • Antonsson B (2001) Bax and other pro-apoptotic Bcl-2 family “killer-proteins” and their victim the mitochondrion. Cell Tissue Res 306(3):347–361

    Article  CAS  PubMed  Google Scholar 

  • Appetecchia M, Baldelli R (2010) Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. J Exp Clin Cancer Res 29(1):19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark PE, Polosukhina D, Love H et al (2011) β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms’ tumors. Am J Pathol 179(6):3045–3055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davenport KP, Blanco FC, Sandler AD (2012) Pediatric malignancies: neuroblastoma, Wilm’s tumor, hepatoblastoma, rhabdomyosarcoma, and sacroccygeal teratoma. Surg Clin N Am 92(3):745–767

    Article  PubMed  Google Scholar 

  • Davidoff AM (2012) Wilms’ tumor. Adv Pediatr 59(1):247–267

    Article  PubMed  PubMed Central  Google Scholar 

  • De Graff SS, Van Gent H, Reitsma-Bierens WC, Van Luyk WH, Dolsma WV, Postma A (1996) Renal function after unilateral nephrectomy for Wilms’ tumour: the influence of radiation therapy. Eur J Cancer 32A(3):465–469

    Article  Google Scholar 

  • Di TM, Casale F, Indolfi P et al (2015) Compensatory hypertrophy and progressive renal damage in children nephrectomized for Wilms’ Tumor. Pediatr Blood Cancer 26(5):325–328

    Google Scholar 

  • Dome JS, Cotton CA, Perlman EJ et al (2006) Treatment of anaplastic histology Wilms’ tumor: results from the fifth National Wilms’ Tumor Study. J Clin Oncol 24(15):2352–2358

    Article  PubMed  Google Scholar 

  • Gadd S, Huff V, Huang CC et al (2012) Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children’s Oncology Group Study. Neoplasia 14(8):742 (IN720–756, IN721)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green DM, Grigoriev YA, Nan B et al (2001) Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 19(7):1926–1934

    Article  CAS  PubMed  Google Scholar 

  • Gregoriadis G, Jain S, Papaioannou I, Laing P (2005) Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids. Int J Pharm 300(1):125–130

    Article  CAS  PubMed  Google Scholar 

  • Iarussi D, Indolfi P, Pisacane C et al (2003) Comparison of left ventricular function by echocardiogram in patients with Wilms’ tumor treated with anthracyclines versus those not so treated. Am J Cardiol 92(3):359–361

    Article  CAS  PubMed  Google Scholar 

  • Jungblut PR, Zimny-Arndt U, Zeindl-Eberhart E et al (1999) Proteomics in human disease: cancer, heart and infectious diseases. Electrophoresis 20(10):2100–2110

  • Kalapurakal JA, Dome JS, Perlman EJ et al (2004) Management of Wilms’ tumour: current practice and future goals. Lancet Oncol 5(1):37–46

    Article  PubMed  Google Scholar 

  • Karoline M, Young K, Sebastian F et al (2013) Targeting cancer with a bi-functional peptide: in vitro and in vivo results. Vivo 27(4):431–442

    Google Scholar 

  • Kawamoto M, Horibe T, Kohno M, Kawakami K (2013) HER2-targeted hybrid peptide that blocks HER2 tyrosine kinase disintegrates cancer cell membrane and inhibits tumor growth in vivo. Mol Cancer Ther 12(4):384–393

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Chung DH (2006) Pediatric solid malignancies: neuroblastoma and Wilms’ Tumor. Surg Clin N Am 86(2):469–487

    Article  PubMed  Google Scholar 

  • Koller CM, Young K, Schmidt-Wolf IGH (2013) Targeting renal cancer with a combination of WNT inhibitors and a bi-functional peptide. Anticancer Res 33(6):2435–2440

    CAS  PubMed  Google Scholar 

  • Korsmeyer SJ (1995) BCL-2 gene family and the regulation of programmed cell death. Cold Spring Harbor Symp Quant Biol 59(3):387

    Google Scholar 

  • Li M-H, Sanchez T, Pappalardo A, Lynch KR, Hla T, Ferrer F (2008) Induction of antiproliferative connective tissue growth factor expression in Wilms’ tumor cells by sphingosine-1-phosphate receptor 2. Mol Cancer Res 6(10):1649–1656

    CAS  PubMed  PubMed Central  Google Scholar 

  • Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20(1):781–810

    Article  CAS  PubMed  Google Scholar 

  • Marjolein VW, Neggers SJCMM, Hein R, Rij CM, Van Rob P, Heuvel-Eibrink MM, Van Den (2011) Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors. PLoS One 7(12):52

    Google Scholar 

  • Neville HL, Ritchey ML (2000) Wilms’ tumor: overview of National Wilms’ Tumor Study Group results. Urol Clin N Am 27(3):435–442

    Article  CAS  Google Scholar 

  • Oberg K (2010) Cancer: antitumor effects of octreotide LAR, a somatostatin analog. Nat Rev Endocrinol 6(4):188

    Article  CAS  PubMed  Google Scholar 

  • Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M (2010) Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg 45(2):387–392

    Article  PubMed  Google Scholar 

  • Paunesku T, Mittal S, Protić M et al (2001) Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int J Radiat Biol 77(10):1007–1021

    Article  CAS  PubMed  Google Scholar 

  • Pode-Shakked N, Dekel B (2011) Wilms tumor—a renal stem cell malignancy? Pediatr Nephrol 26(9):1535–1543

    Article  PubMed  Google Scholar 

  • Qian Z, Jiaxiang W, Rui D, Shaobo Y, Shu Z (2011) Identification of novel serum biomarkers in child nephroblastoma using proteomics technology. Mol Biol Rep 38(1):631–638

    Article  CAS  Google Scholar 

  • Schweigert A, Fischer C, Mayr D, von Schweinitz D, Kappler R, Hubertus J (2016) Activation of the Wnt/β-catenin pathway is common in wilms tumor, but rarely through β-catenin mutation and APC promoter methylation. Pediatr Surg Int 32(12):1141–1146

    Article  PubMed  Google Scholar 

  • Wang JX, Zhang J, Liu QL, Wang L, Fan YZ, Jie-Kai YU (2006) Detecting biomarkers from serum in nephroblastoma patients with support vector machine. Zhonghua Yi Xue Za Zhi 86(42):2982

    CAS  PubMed  Google Scholar 

  • Zhang B, Wang J, Yu J, Zheng S (2009) A serum protein fingerprint in the diagnosis and prognosis of Wilms’ tumors in children. Life Sci J 6(1):27–32

    CAS  Google Scholar 

  • Zhang Q, Yan S et al (2010) Detection of biomarkers in children with Wilms' tumor using proteinchip technology. Chin Med J 123(14):1939

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was conducted within the Department of Pediatric Surgery supported by the First Affiliated Hospital of Zhengzhou University. The study was financially supported by the National Natural Science Foundation of China (81172085, 81071782). We thank all of the patients participating in the study.

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Authors and Affiliations

  1. Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Erqi District, Zhengzhou, 450000, Henan, China

    Wei Zhao, Fei Guo, Pengfei Gao, Junjie Zhang, Lei Wang, Da Zhang, Pan Qin & Jiaxiang Wang

  2. Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Erqi District, Zhengzhou, 450000, Henan, China

    Juan Li & Ping Li

  3. Department of Urinary Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Erqi District, Zhengzhou, 450000, Henan, China

    Zechen Yan

  4. Department of Microbiology and Immunology, Basic Medical College, Zhengzhou University, No. 100 Kexuedadao Road, Zhongyuan District, Zhengzhou, 450001, Henan, China

    Guoqiang Zhao

Authors
  1. Wei Zhao
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  2. Juan Li
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  3. Ping Li
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  4. Fei Guo
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  8. Lei Wang
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  9. Da Zhang
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  10. Pan Qin
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  11. Guoqiang Zhao
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Contributions

JW and WZ carried out the experiments design, theoretical simulations and data analysis. WZ and JL carried out test operation in animal experiment and cell experiment. PL carried out measurements. WZ and JL wrote the manuscript. ZY, LW and JZ revised the manuscript. DZ, PQ, FG, PG and GZ gave scientific advices. All the authors contributed through scientific discussion and reviewed the manuscript.

Corresponding author

Correspondence to Jiaxiang Wang.

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Zhao, W., Li, J., Li, P. et al. Wilms tumor-suppressing peptide inhibits proliferation and induces apoptosis of Wilms tumor cells in vitro and in vivo. J Cancer Res Clin Oncol 145, 2457–2468 (2019). https://doi.org/10.1007/s00432-019-03003-0

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