Skip to main content

Advertisement

SpringerLink
Log in

WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma

  • Research Article
  • Published:
Tumor Biology

Abstract

Whelming evidence has demonstrated that WW domain containing E3 ubiquitin protein ligase 1 (WWP1) participates in a wide variety of biological processes and is tightly related to the initiation and progression of many tumors. Currently, although mounting evidence supports a role of WWP1 in tumor promotion and tumorigenesis, the potential roles of WWP1 and its biological functions in gastric carcinoma are not fully understood. Here, we found that WWP1 messenger RNA (mRNA) and protein were highly expressed in gastric carcinoma tissues and cells. High WWP1 mRNA and protein levels were tightly related to differentiation status, TNM stage, invasive depth, lymph node metastasis, and poor prognosis in gastric carcinoma. Furthermore, WWP1 siRNA significantly decreased WWP1 protein level in MKN-45 and AGS cells; meanwhile, WWP1 depletion markedly inhibited tumor proliferation in vitro and in vivo, arrested cell cycle at G0/G1 phase, and induced cell apoptosis in MKN-45 and AGS cells. Most notably, WWP1 downregulation both inactivated PTEN-Akt signaling pathway in MKN-45 and AGS cells. Taken altogether, our findings suggest that WWP1 acts as an oncogenic factor and should be considered as a novel interfering molecular target for gastric carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Gomceli I, Demiriz B, Tez M. Gastric carcinogenesis. World J Gastroenterol. 2012;18(37):5164–70.

    PubMed  PubMed Central  Google Scholar 

  2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.

    Article  PubMed  Google Scholar 

  3. Guggenheim DE, Shah MA. Gastric cancer epidemiology and risk factors. J Surg Oncol. 2013;107(3):230–6.

    Article  PubMed  Google Scholar 

  4. Roukos DH. Targeting gastric cancer with trastuzumab: new clinical practice and innovative developments to overcome resistance. Ann Surg Oncol. 2010;17(1):14–7.

    Article  PubMed  Google Scholar 

  5. Verdecchia A, Corazziari I, Gatta G, Lisi D, Faivre J, Forman D. Explaining gastric cancer survival differences among European countries. Int J Cancer. 2004;109(5):737–41.

    Article  CAS  PubMed  Google Scholar 

  6. Kaneko S, Yoshimura T. Time trend analysis of gastric cancer incidence in Japan by histological types, 1975-1989. Br J Cancer. 2001;84(3):400–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Malbert-Colas L, Fay M, Cluzeaud F, Blot-Chabaud M, Farman N, Dhermy D, et al. Differential expression and localisation of WWP1, a Nedd4-like protein, in epithelia. Pflugers Arch. 2003;447(1):35–43.

    Article  CAS  PubMed  Google Scholar 

  8. Porkka K, Saramaki O, Tanner M, Visakorpi T. Amplification and overexpression of Elongin C gene discovered in prostate cancer by cDNA microarrays. Lab Invest. 2002;82(5):629–37.

    Article  CAS  PubMed  Google Scholar 

  9. Chen C, Zhou Z, Ross JS, Zhou W, Dong JT. The amplified WWP1 gene is a potential molecular target in breast cancer. Int J Cancer. 2007;121(1):80–7.

    Article  CAS  PubMed  Google Scholar 

  10. Chen C, Sun X, Guo P, Dong XY, Sethi P, Zhou W, et al. Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer. Oncogene. 2007;26(16):2386–94.

    Article  CAS  PubMed  Google Scholar 

  11. Balleine RL, Fejzo MS, Sathasivam P, Basset P, Clarke CL, Byrne JA. The hD52 (TPD52) gene is a candidate target gene for events resulting in increased 8q21 copy number in human breast carcinoma. Genes Chromosomes Cancer. 2000;29(1):48–57.

    Article  CAS  PubMed  Google Scholar 

  12. Verdecia MA, Joazeiro CA, Wells NJ, Ferrer JL, Bowman ME, Hunter T, et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell. 2003;11(1):249–59.

    Article  CAS  PubMed  Google Scholar 

  13. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci U S A. 1995;92(11):5249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bernassola F, Karin M, Ciechanover A, Melino G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell. 2008;14(1):10–21.

    Article  CAS  PubMed  Google Scholar 

  15. Zhi X, Chen C. WWP1: a versatile ubiquitin E3 ligase in signaling and diseases. Cell Mol Life Sci. 2012;69(9):1425–34.

    Article  CAS  PubMed  Google Scholar 

  16. Yeung B, Ho KC, Yang X. WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells. PLoS One. 2013;8(4):e61027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cao X, Xue L, Han L, Ma L, Chen T, Tong T. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) delays cellular senescence by promoting p27(Kip1) degradation in human diploid fibroblasts. J Biol Chem. 2011;286(38):33447–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, et al. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene. 2004;23(41):6914–23.

    Article  CAS  PubMed  Google Scholar 

  19. Cheng Q, Cao X, Yuan F, Li G, Tong T. Knockdown of WWP1 inhibits growth and induces apoptosis in hepatoma carcinoma cells through the activation of caspase3 and p53. Biochem Biophys Res Commun. 2014;448(3):248–54.

    Article  CAS  PubMed  Google Scholar 

  20. Lin JH, Hsieh SC, Chen JN, Tsai MH, Chang CC. WWP1 gene is a potential molecular target of human oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116(2):221–31.

    Article  PubMed  Google Scholar 

  21. Hauber HP, Manoukian JJ, Nguyen LH, Sobol SE, Levitt RC, Holroyd KJ, et al. Increased expression of interleukin-9, interleukin-9 receptor, and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis. Laryngoscope. 2003;113(6):1037–42.

    Article  CAS  PubMed  Google Scholar 

  22. Liu Y, Li K, Ren Z, Li S, Zhang H, Fan Q. Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma. J Histochem Cytochem. 2012;60(7):512–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Suehara Y, Kondo T, Fujii K, Hasegawa T, Kawai A, Seki K, et al. Proteomic signatures corresponding to histological classification and grading of soft-tissue sarcomas. Proteomics. 2006;6(15):4402–9.

    Article  CAS  PubMed  Google Scholar 

  24. Huang CY, Chen YM, Zhao JJ, Chen YB, Jiang SS, Yan SM, et al. Decreased expression of transcription elongation factor A-like 7 is associated with gastric adenocarcinoma prognosis. PLoS One. 2013;8(1):e54671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu D, Zhang L, Shen Z, Tan F, Hu Y, Yu J, et al. Increased levels of SLP-2 correlate with poor prognosis in gastric cancer. Gastric Cancer. 2013;16(4):498–504.

    Article  CAS  PubMed  Google Scholar 

  26. Liu HT, Wang N, Wang X, Li SL. Overexpression of Pim-1 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. J Surg Oncol. 2010;102(6):683–8.

    Article  CAS  PubMed  Google Scholar 

  27. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35(7):1732–7.

    Article  CAS  PubMed  Google Scholar 

  28. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  29. Lu Z, Liu H, Xue L, Xu P, Gong T, Hou G. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706. Int J Oncol. 2008;32(3):643–51.

    CAS  PubMed  Google Scholar 

  30. Yan L, Li S, Xu C, Zhao X, Hao B, Li H, et al. Target protein for Xklp2 (TPX2), a microtubule-related protein, contributes to malignant phenotype in bladder carcinoma. Tumour Biol. 2013;34(6):4089–100.

    Article  CAS  PubMed  Google Scholar 

  31. Liu J, Wan L, Liu P, Inuzuka H, Wang Z, Wei W. SCF(beta-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway. Oncotarget. 2014;5(4):1026–37.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wei Z, Cui L, Mei Z, Liu M. Zhang D: miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway. FEBS Lett. 2014;588(9):1773–9.

    Article  CAS  PubMed  Google Scholar 

  33. Liao C, Chen W, Fan X, Jiang X, Qiu L, Chen C, et al. MicroRNA-200c inhibits apoptosis in pituitary adenoma cells by targeting the PTEN/Akt signaling pathway. Oncol Res. 2014;21(3):129–36.

    Article  CAS  Google Scholar 

  34. Li Y, Zhou Z, Chen C. WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis. Cell Death Differ. 2008;15(12):1941–51.

    Article  CAS  PubMed  Google Scholar 

  35. Nguyen Huu NS, Ryder WD, Zeps N, Flasza M, Chiu M, Hanby AM, et al. Tumour-promoting activity of altered WWP1 expression in breast cancer and its utility as a prognostic indicator. J Pathol. 2008;216(1):93–102.

    Article  CAS  PubMed  Google Scholar 

  36. Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, et al. Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res. 2006;66(16):8210–8.

    Article  CAS  PubMed  Google Scholar 

  37. Peschiaroli A, Scialpi F, Bernassola F, El Sherbini el S, Melino G. The E3 ubiquitin ligase WWP1 regulates DeltaNp63-dependent transcription through Lys63 linkages. Biochem Biophys Res Commun. 2010;402(2):425–30.

    Article  CAS  PubMed  Google Scholar 

  38. Seo SR, Lallemand F, Ferrand N, Pessah M, L’Hoste S, Camonis J, et al. The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation. EMBO J. 2004;23(19):3780–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li Y, Zhou Z, Alimandi M, Chen C. WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer. Oncogene. 2009;28(33):2948–58.

    Article  CAS  PubMed  Google Scholar 

  40. Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, et al. The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation. Mol Cell Biol. 2009;29(3):892–906.

    Article  CAS  PubMed  Google Scholar 

  41. Paez J, Sellers WR. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res. 2003;115:145–67.

    Article  CAS  PubMed  Google Scholar 

  42. Cheng GZ, Park S, Shu S, He L, Kong W, Zhang W, et al. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets. 2008;8(1):2–6.

    Article  CAS  PubMed  Google Scholar 

  43. Chen C, Matesic LE. The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev. 2007;26(3–4):587–604.

    Article  CAS  PubMed  Google Scholar 

  44. Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007;128(1):141–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE, et al. Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem. 2003;278(30):28258–63.

    Article  CAS  PubMed  Google Scholar 

  46. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007;128(1):129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Basic Medical College of Zhengzhou University, 100 Kexue Road, Zhengzhou, Henan, 450001, China

    Li Zhang & Qinxian Zhang

  2. Department of Reproductive Technology, Henan Provincial Research Institute for Population and Family Planning, Zhengzhou, Henan, 450002, China

    Zongyin Wu

  3. Department of Anatomy, Basic Medical College of Zhengzhou University, Zhengzhou, Henan, 450001, China

    Zhao Ma

  4. College of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China

    Hongtao Liu & Yahong Wu

Authors
  1. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zongyin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongtao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yahong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qinxian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qinxian Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Wu, Z., Ma, Z. et al. WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma. Tumor Biol. 36, 787–798 (2015). https://doi.org/10.1007/s13277-014-2696-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2696-0

Keywords

Search

Navigation