Skip to main content

Advertisement

Log in

Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. RON is a transmembrane receptor overexpressed in various cancers; however, the clinical significance of its phosphorylated form (pRON) is not fully deciphered. This report is the first to investigate the expression and clinical significance of pRON in human ESCC. Quantitative polymerase chain reaction revealed an up-regulation of RON mRNA in 70% (7/10) of ESCC tissues when compared to the adjacent nontumor tissues. An overexpression of pRON protein was found in most of the ESCC cell lines studied (4/5) when compared to two non-neoplastic esophageal epithelial cells using immunoblot. In 64 ESCC tissues, pRON was localized at the cell membrane, cytoplasm and nucleus in 15 (23.4%), 63 (98.4%) and 61 (95.3%) cases using immunohistochemistry. Patients having high expression of cytoplasmic pRON significantly associated with shorter median survival when compared to those with low expression (25.41 months vs. 14.43 months), suggesting cytoplasmic pRON as a potential marker for poor prognosis in ESCC patients.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Anderson LL, Lad TE. Autopsy findings in squamous-cell carcinoma of the esophagus. Cancer. 1982;50(8):1587–90.

    Article  PubMed  CAS  Google Scholar 

  3. Wang MH, et al. Identification of the RON gene product as the receptor for the human macrophage stimulating protein. Science. 1994;266(5182):117–9.

    Article  PubMed  CAS  Google Scholar 

  4. Iwama A, Yamaguchi N, Suda T. STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family. EMBO J. 1996;15(21):5866–75.

    PubMed  CAS  Google Scholar 

  5. Peace BE, et al. Point mutations and overexpression of RON induce transformation, tumor formation, and metastasis. Oncogene. 2001;20(43):6142–51.

    Article  PubMed  CAS  Google Scholar 

  6. Wang MH, et al. Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes. Exp Cell Res. 1996;226(1):39–46.

    Article  PubMed  CAS  Google Scholar 

  7. Thomas RM, et al. The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. Cancer Res. 2007;67(13):6075–82.

    Article  PubMed  CAS  Google Scholar 

  8. Hsu PY, et al. Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol. 2006;176(5):2262–7.

    Article  PubMed  CAS  Google Scholar 

  9. Wang MH, Kurtz AL, Chen Y. Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis. 2000;21(8):1507–12.

    Article  PubMed  CAS  Google Scholar 

  10. Okino T, et al. Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa. Int J Oncol. 1999;15(4):709–14.

    PubMed  CAS  Google Scholar 

  11. Cheng HL, et al. Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer. 2005;92(10):1906–14.

    Article  PubMed  CAS  Google Scholar 

  12. Camp ER, et al. Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target. Cancer. 2007;109(6):1030–9.

    Article  PubMed  CAS  Google Scholar 

  13. Cheung LC, et al. Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line HKESC-4 of Chinese origin. Cancer Genet Cytogenet. 2007;178(1):17–25.

    Article  PubMed  CAS  Google Scholar 

  14. Hu YC, et al. Establishment, characterization, karyotyping, and comparative genomic hybridization analysis of HKESC-2 and HKESC-3: two newly established human esophageal squamous cell carcinoma cell lines. Cancer Genet Cytogenet. 2002;135(2):120–7.

    Article  PubMed  CAS  Google Scholar 

  15. Tang JC, et al. Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line SLMT-1 of Chinese origin. Cancer Genet Cytogenet. 2001;124(1):36–41.

    Article  PubMed  CAS  Google Scholar 

  16. Hu Y, et al. Establishment and characterization of HKESC-1, a new cancer cell line from human esophageal squamous cell carcinoma. Cancer Genet Cytogenet. 2000;118(2):112–20.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang H, et al. Cytogenetic aberrations in immortalization of esophageal epithelial cells. Cancer Genet Cytogenet. 2006;165(1):25–35.

    Article  PubMed  CAS  Google Scholar 

  18. Zhang H, et al. Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation. Cancer Lett. 2007;245(1–2):184–94.

    Article  PubMed  CAS  Google Scholar 

  19. Lee NP, et al. Comparative proteomic analysis of mouse livers from embryo to adult reveals an association with progression of hepatocellular carcinoma. Proteomics. 2008;8(10):2136–49.

    Article  PubMed  CAS  Google Scholar 

  20. Lee NP, et al. Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int J Cancer. 2010;127(4):968–76.

    PubMed  CAS  Google Scholar 

  21. Lee NP, et al. Kidney claudin-19: localization in distal tubules and collecting ducts and dysregulation in polycystic renal disease. FEBS Lett. 2006;580(3):923–31.

    Article  PubMed  CAS  Google Scholar 

  22. Lee NP, et al. Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma. J Proteome Res. 2009;8(3):1293–303.

    Article  PubMed  CAS  Google Scholar 

  23. Liu LX, et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology. 2009;50(5):1453–63.

    Article  PubMed  CAS  Google Scholar 

  24. Chung Y, et al. Altered E-cadherin expression and p120 catenin localization in esophageal squamous cell carcinoma. Ann Surg Oncol. 2007;14(11):3260–7.

    Article  PubMed  Google Scholar 

  25. Wang MH, et al. Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumourigenic phenotypes in thyroid cancer cells. J Pathol. 2007;213(4):402–11.

    Article  PubMed  CAS  Google Scholar 

  26. Nakai K, Horton P. PSORT a program for detecting sorting signals in proteins and predicting their subcellular localization. Trends Biochem Sci. 1999;24(1):34–6.

    Article  PubMed  CAS  Google Scholar 

  27. Lee WY, et al. Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(6):2222–8.

    Article  CAS  Google Scholar 

  28. Rampino T, et al. The Ron proto-oncogene product is a phenotypic marker of renal oncocytoma. Am J Surg Pathol. 2003;27(6):779–85.

    Article  PubMed  Google Scholar 

  29. Kaku N, et al. Characterization of nuclear import of the domain-specific androgen receptor in association with the importin alpha/beta and Ran-guanosine 5′-triphosphate systems. Endocrinology. 2008;149(8):3960–9.

    Article  PubMed  CAS  Google Scholar 

  30. Schlessinger J, Lemmon MA. Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Cell. 2006;127(1):45–8.

    Article  PubMed  CAS  Google Scholar 

  31. Lin SY, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2001;3(9):802–8.

    Article  PubMed  CAS  Google Scholar 

  32. Pozner-Moulis S, Pappas DJ, Rimm DL. Met, the hepatocyte growth factor receptor, localizes to the nucleus in cells at low density. Cancer Res. 2006;66(16):7976–82.

    Article  PubMed  CAS  Google Scholar 

  33. Ni CY, et al. Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001;294(5549):2179–81.

    Article  PubMed  CAS  Google Scholar 

  34. Lee HJ, et al. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem. 2002;277(8):6318–23.

    Article  PubMed  CAS  Google Scholar 

  35. Lange A, et al. Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007;282(8):5101–5.

    Article  PubMed  CAS  Google Scholar 

  36. Chen YQ, et al. Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res. 2000;261(1):229–38.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Simon Law.

Additional information

Marco K. C. Hui and Kenneth K. Y. Lai contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12032_2011_112_MOESM1_ESM.tiff

Supplementary Figure 1. NLS in human RON protein. PSORT II was used to predict NLS in human RON protein, and five putative NLSs were located (underlined). Four of them were consecutive in the amino-terminal region, while one was found at the carboxyl-terminus. (TIFF 156 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hui, M.K.C., Lai, K.K.Y., Chan, K.W. et al. Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma. Med Oncol 29, 1699–1706 (2012). https://doi.org/10.1007/s12032-011-0112-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-011-0112-9

Keywords

Navigation