Advertisement

Tumor Biology

, Volume 37, Issue 1, pp 627–631 | Cite as

The ubiquitin ligase RNF43 downregulation increases membrane expression of frizzled receptor in pancreatic ductal adenocarcinoma

  • Dadong Wang
  • Jingwang Tan
  • Yong Xu
  • Mingming Han
  • Yuliang Tu
  • Ziman Zhu
  • Chunqing Dou
  • Jin Xin
  • Xianglong Tan
  • Jian-ping Zeng
  • Gang Zhao
  • Zhiwei Liu
Research Article

Abstract

RNF43 is a novel tumor suppressor protein and known to be expressed in a multitude of tissue and dysregulated in cancers of these organs including ovarian and colorectal tissues. RNF43 expression has been shown to be expressed in mutated forms in several pancreatic cell lines. RNF43, by virtue of being an ubiquitin ligase, has the potential to ubiquitinylate membrane receptors like frizzled that subserves sensing Wnt soluble signals at the cell membrane. Thus, normally, RNF43 downregulates Wnt signaling by removing frizzled receptor from the membrane. In the present study, the expression of the tumor suppressor RNF43 was examined in human patient samples of pancreatic ductal adenocarcinoma (PDAC). Reduced levels of expression of RNF43 in PDAC were demonstrated by Western blotting. We incorporated membrane biotinylation assay to examine the expression of frizzled6 receptor in the membrane and demonstrated that it is significantly increased in PDAC tissues. This may be responsible for enhanced Wnt/beta-catenin signaling and provides the first level of evidence of a possible role of this well-known pathway in pancreatic exocrine carcinogenesis. We have utilized appropriate controls to ensure the true positivity of the findings of the present study. The contribution of Wnt/beta-catenin/RNF43 pathway in pancreatic carcinogenesis may provide for utilization of pharmacologic resources for precision-based approaches to treat pancreatic ductal adenocarcinoma.

Keywords

Tumor suppressor Pancreas Tumor progression Wnt signaling 

Notes

Conflict of interest

None

References

  1. 1.
    Amato E, Molin MD, Mafficini A, Yu J, Malleo G, Rusev B, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol. 2014;233:217–27.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Cowan RW, Maitra A. Genetic progression of pancreatic cancer. Cancer J. 2014;20(1):80–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Valsangkar NP, Ingkakul T, Correa-Gallego C, Mino-Kenudson M, Masia R, Lillemoe KD, et al. Survival in ampullary cancer: potential role of different KRAS mutations. Surgery. 2015;157:260–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wang L, Yang H, Abel EV, Ney GM, Palmbos PL, Bednar F, et al. ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. Genes Dev. 2015;29:171–83.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kruger S, Haas M, Ormanns S, Bächmann S, Siveke JT, Kirchner T, et al. Translational research in pancreatic ductal adenocarcinoma: current evidence and future concepts. World J Gastroenterol. 2014;20:10769–77.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Fiorini C, Cordani M, Padroni C, Blandino G, Di Agostino S, Donadelli M. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta. 1853;2015:89–100.Google Scholar
  7. 7.
    Liszka L. Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis. Pol J Pathol. 2014;65:100–12.CrossRefPubMedGoogle Scholar
  8. 8.
    Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488:665–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, et al. RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J Pathol. 2013;229:469–76.CrossRefPubMedGoogle Scholar
  10. 10.
    Gala MK, Mizukami Y, Le LP, Moriichi K, Austin T, Yamamoto M, et al. Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology. 2014;146:520–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Reid MD, Choi H, Balci S, Akkas G, Adsay V. Serous cystic neoplasms of the pancreas: clinicopathologic and molecular characteristics. Semin Diagn Pathol. 2014;31:475–83.CrossRefPubMedGoogle Scholar
  12. 12.
    Sakamoto H, Kuboki Y, Hatori T, Yamamoto M, Sugiyama M, Shibata N, et al. Clinicopathological significance of somatic RNF43 mutation and aberrant expression of ring finger protein 43 in intraductal papillary mucinous neoplasms of the pancreas. Mod Pathol. 2015;28:261–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Wu J, Jiao Y, Dal Molin M, Maitra A, Maitra A, de Wilde RF, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011;108:21188–93.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 2013;110:12649–54.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 1843;2014:47–60.Google Scholar
  16. 16.
    Hall Pde L, Wilentz RE, de Klerk W, Bornman PP. Premalignant conditions of the pancreas. Pathology. 2002;34:504–17.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang HH, Xie NN, Li QY, Hu YQ, Ren JL, Guleng B. Exome sequencing revealed novel germline mutations in Chinese Peutz-Jeghers syndrome patients. Dig Dis Sci. 2014;59:64–71.CrossRefPubMedGoogle Scholar
  18. 18.
    Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, et al. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232:428–35.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wall I, Schmidt-Wolf IG. Effect of Wnt inhibitors in pancreatic cancer. Anticancer Res. 2014;34:5375–80.PubMedGoogle Scholar
  20. 20.
    Jiang H, Li Q, He C, Li F, Sheng H, Shen X, et al. Activation of the Wnt pathway through Wnt2 promotes metastasis in pancreatic cancer. Am J Cancer Res. 2014;4:537–44.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJ, et al. Secreted frizzled related proteins: implications in cancers. Biochim Biophys Acta. 1845;2014:53–65.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Dadong Wang
    • 1
  • Jingwang Tan
    • 1
  • Yong Xu
    • 1
  • Mingming Han
    • 1
  • Yuliang Tu
    • 1
  • Ziman Zhu
    • 1
  • Chunqing Dou
    • 1
  • Jin Xin
    • 1
  • Xianglong Tan
    • 1
  • Jian-ping Zeng
    • 1
  • Gang Zhao
    • 2
  • Zhiwei Liu
    • 3
  1. 1.Department of Hepatobiliary SurgeryThe First Affiliated Hostpial of Chinese PLA General HospitalBeijingChina
  2. 2.Department of Emergency SurgeryQianfoshang Hospital Affiliated to Shandong UniversityJinanChina
  3. 3.Department of Hepatobiliary SurgeryChinese PLA General HospitalBeijingChina

Personalised recommendations