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RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells

Oncogene volume 23, pages 8464–8474 (2004)Cite this article

Abstract

Altered expression of receptor tyrosine kinases contributes to tumorigenic behaviors of epithelial cancers. In this study, the pathogenic roles of receptor tyrosine kinase RON (recepteur d'origine nantais) in regulating oncogenic phenotypes in colorectal epithelial cells were studied. Increased expression of RON and its variants resulted in colony formation and motile activities of colonic epithelial AA/C1 cells as evident in soft-agar and migration assays, respectively. These results suggest that overexpression of wild-type RON mediates the transformed phenotypes in immortalized colon epithelial cells. In colorectal cancer cells (HT-29, HCT116, and SW620) that naturally express RON, the RON gene expression was silenced by RNA interference. The introduction of RON-specific small interfering (si) RNA significantly affected cancer cell proliferation, motility, and led to increased apoptotic cell death. Focus-forming activities and anchorage-independent growth of colon cancer cells were also dramatically reduced. Moreover, it was demonstrated in tumor growth assays that silencing RON gene expression significantly reduces tumorigenic activities of SW620 cells in vivo. By analysing signaling proteins involved in colon carcinogenesis, we found that the effect of RON-specific siRNA is associated with diminished expression of β-catenin, a critical component in the Wnt signaling pathway. Taken together, our results demonstrate that altered expression of RON in colon cancer cells is required to maintain tumorigenic phenotypes. Thus, silencing RON gene expression could have potential to reverse malignant activities of colon tumors in vivo.

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Acknowledgements

This work was performed in part at the University of Colorado School of Medicine. We thank Drs C Gespach (Hôpital Saint-Antoine, Paris, France) for AA/C1 cells; G Gaudino (Universita di Torino, Novara, Italy) for the RONm1254t cDNA; and EJ Leonard (National Cancer Institute, Frederick, MD, USA) for human MSP. We also thank Dr JS Lindsey (Texas Tech University Health Sciences Center) for critical reading of the manuscript. This work was supported by NIH Grants R01 CA91980, Amarillo Area Foundation, and Foundation of Cheung Kong Scholars Program from the Ministry of Education, PR China.

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  1. Laboratory of Cheung Kong Scholars Program for Biomedical Sciences, Institute of Infectious Diseases, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, PR, China

    Xiang-Ming Xu & Ming-Hai Wang

  2. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, 79106, TX, USA

    Xiang-Ming Xu, Da Wang, Qi Shen, Yi-Qing Chen & Ming-Hai Wang

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Correspondence to Ming-Hai Wang.

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Xu, XM., Wang, D., Shen, Q. et al. RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. Oncogene 23, 8464–8474 (2004). https://doi.org/10.1038/sj.onc.1207907

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