Abstract
The RON receptor tyrosine kinase is a member of the MET proto-oncogene family that has been implicated in regulating motile-invasive phenotypes in certain types of epithelial cancers. The purpose of this study was to determine if RON expression is altered in primary human colorectal adenocarcinomas. Results from immunohistochemical staining showed that RON is highly expressed in the majority of colorectal adenocarcinomas (29/49 cases). Accumulated RON is also constitutively active with autophosphorylation in tyrosine residues. Moreover, three splicing variants of RON, namely RONΔ165, RONΔ160, and RONΔ155 were detected and cloned from two primary colon cancer samples. These RON variants were generated by deletions in different regions in extracellular domains of the RON β chain. Functional studies showed that expression of RONΔ160 or RONΔ155 in Martin–Darby canine kidney cells resulted in increased cell dissociation (scatter-like activity). RON variants, RONΔ160 and RONΔ155, also exerted the ability to induce multiple focus formation and sustain anchorage-independent growth of transfected NIH3T3 cells. Moreover, NIH3T3 cells expressing RONΔ160 or RONΔ155 formed tumors in athymic nude mice and colonized in the lungs. These data suggest that RON expression is altered in certain primary colon cancers. Abnormal accumulation of RON variants may play a role in the progression of certain colorectal cancers in vivo.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Allred DC, Harvey JM, Berardo M and Clark GM . (1998). Mod. Pathol., 11, 155–168.
Angeloni D, Danilkovitch A, Ivanov SV, Breathnach R, Johnson BE, Leonard EJ and Lerman MI . (2000). Genes Chromosomes Cancer, 29, 147–156.
Birchmeier W, Brinkmann V, Niemann C, Meiners S, DiCesare S, Naundorf H and Sachs M . (1997). Ciba Found. Symp., 212, 230–240.
Chen Y-Q, Zhou Y-Q, Angeloni-Andreazzoli D, Kurtz AL, Qiang X-Z and Wang M-H . (2000). Exp. Cell Res., 261, 229–238.
Collesi C, Santoro MM, Gaudino G and Comoglio PM . (1996). Mol. Cell. Biol., 16, 5518–5526.
Comoglio PM, Tamagnone L and Boccaccio C . (1999). Exp. Cell Res., 253, 88–99.
Crawford JM . (1994). Pathological Basis of Disease: The Gastrointestinal Tract. Cotran RZ, Kumar V, Robbins SL (eds). WB Saunders: Philadelphia, PA, pp. 755–829.
Dorudi S and Hart IR . (1993). Curr. Opin. Oncol., 5, 130–135.
Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, Godowski PJ and Comoglio PM . (1994). EMBO J., 13, 3524–3532.
Greenlee RT, Murray T, Bolden S and Wingo PA . (2000). CA Cancer J. Clin., 50, 7–33.
Han S, Stuart LA and Degen SJF . (1991). Biochemistry, 30, 9768–9780.
Iwama A, Okano K, Sudo T, Matsuda Y and Suda T (1994). Blood, 83, 3160–3169.
Kinzler KW and Vogelstein B . (1998). The Genetic Basis of Human Cancer: Colorectal Tumors. Vogelstein B, Kinzler KW (eds). McGraw-Hill: New York, pp. 565–587.
Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P and Comoglio PM . (1998). Oncogene, 16, 2927–2933.
Montero-Julian FA, Dauny I, Flavetta S, Ronsin C, Andre F, Xerri L, Wang M-H, Marvaldi J, Breathnach R and Brailly H . (1998). Hybridoma, 17, 541–551.
Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa K, Nakano S, Akagi J, Sakamoto O, Suda T and Ogawa M . (1999). Int. J. Oncol., 13, 709–414.
Peace BE, Hughes MJ, Degen SJF and Waltz SE . (2001). Oncogene, 20, 6142–6151.
Porter AC and Vaillancourt RR . (1998). Oncogene, 17, 1343–1152.
Portera Jr CA, Berman RS and Ellis LM . (1988). Surg. Oncol., 7, 183–195.
Ronsin C, Muscatelli F, Mattei MG and Breathnach R . (1993). Oncogene, 8, 1195–1202.
Rubin JS, Bottaro DP and Aaronson SA . (1993). Biochem. Biophys. Acta, 1155, 357–364.
Santoro MM, Collesi C, Grisendi S, Gaudino G and Comoglio PM . (1996). Mol. Cell. Biol., 16, 7072–7083.
Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M and Gaudino G . (1998). Oncogene, 17, 741–749.
Skeel A, Yoshimura T, Showalter SD, Tanaka S, Appella E and Leonard EJ . (1991). J. Exp. Med., 173, 1227–1234.
Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I and Resau J . (1997). Ciba Found. Symp., 212, 119–130.
Wang M-H, Kurtz AL and Chen Y-Q . (2000). Carcinogenesis, 21, 1507–1512.
Wang M-H, Ronsin C, Gesnel MC, Coupeym L, Skeel A, Leonard EJ and Breathnach R . (1994a). Science, 266, 117–119.
Wang M-H, Yoshimura T, Skeel A and Leonard EJ . (1994b). J. Biol. Chem., 269, 3436–3440.
Williams TA, Longati P, Pugliese L, Gual P, Bardelli A and Michieli P . (1999). J. Cell. Physiol., 181, 507–514.
Xiao Z-Q, Chen Y-Q and Wang M-H . (2000). Biochem. Biophy. Res. Commun., 267, 669–675.
Yokota J . (1999). Carcinogenesis, 21, 497–503.
Acknowledgements
This work was performed in University of Colorado School of Medicine. We thank Drs EJ Leonard (National Cancer Institute of NIH, Frederick, MD, USA) for providing human MSP, G Gaudino (Universita di Torino, Novara, Italy) for RON-M1254T cDNA, and J Fisher (University of Colorado Health Sciences Center, Denver, CO, USA) for critical comments. We are grateful to Ms J Larson (Denver Health Medical Center, Denver, CO, USA) for editing the manuscript. The assistance from the staffs in the Department of Pathology at UCHSC and Denver Health Medical Center is greatly appreciated. This study was supported by NIH Grants R01 AI43516 and R01 CA91980 to MHW.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhou, YQ., He, C., Chen, YQ. et al. Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 22, 186–197 (2003). https://doi.org/10.1038/sj.onc.1206075
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206075
Keywords
This article is cited by
-
MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation
Journal of Experimental & Clinical Cancer Research (2024)
-
Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy
Cell Death & Differentiation (2023)
-
Nonsense-mediated RNA decay and its bipolar function in cancer
Molecular Cancer (2021)
-
MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy
Journal of Experimental & Clinical Cancer Research (2020)
-
The HNRNPA2B1–MST1R–Akt axis contributes to epithelial-to-mesenchymal transition in head and neck cancer
Laboratory Investigation (2020)