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Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential

Oncogene volume 22, pages 186–197 (2003)Cite this article

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.

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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.

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Authors and Affiliations

  1. Division of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China

    Yong-Qing Zhou & Ming-Hai Wang

  2. Department of Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China

    Chao He

  3. Department of Medicine and CU Cancer Center, University of Colorado School of Medicine, Denver, CO, USA

    Yi-Qing Chen, Dong Wang & Ming-Hai Wang

  4. Department of Medicine, Denver Health Medical Center, Denver, 80204, CO, USA

    Ming-Hai Wang

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Correspondence to Ming-Hai Wang.

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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

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