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.
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References
Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Anderson LL, Lad TE. Autopsy findings in squamous-cell carcinoma of the esophagus. Cancer. 1982;50(8):1587–90.
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.
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.
Peace BE, et al. Point mutations and overexpression of RON induce transformation, tumor formation, and metastasis. Oncogene. 2001;20(43):6142–51.
Wang MH, et al. Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes. Exp Cell Res. 1996;226(1):39–46.
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.
Hsu PY, et al. Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol. 2006;176(5):2262–7.
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.
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.
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.
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.
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.
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.
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.
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.
Zhang H, et al. Cytogenetic aberrations in immortalization of esophageal epithelial cells. Cancer Genet Cytogenet. 2006;165(1):25–35.
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.
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.
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.
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.
Lee NP, et al. Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma. J Proteome Res. 2009;8(3):1293–303.
Liu LX, et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology. 2009;50(5):1453–63.
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.
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.
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.
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.
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.
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.
Schlessinger J, Lemmon MA. Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Cell. 2006;127(1):45–8.
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.
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.
Ni CY, et al. Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001;294(5549):2179–81.
Lee HJ, et al. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem. 2002;277(8):6318–23.
Lange A, et al. Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007;282(8):5101–5.
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.
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Marco K. C. Hui and Kenneth K. Y. Lai contributed equally to this work.
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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)
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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
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DOI: https://doi.org/10.1007/s12032-011-0112-9