Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumourigenic phenotypes in thyroid cancer cells.
Aberrant expression of the RON receptor tyrosine kinase has been implicated in the pathogenesis of epithelial tumours. The aim of this study was to determine RON expression in various normal epithelial cells and their corresponding tumours by immunohistochemistry. The role of RON in regulating tumourigenic phenotypes was also studied using thyroid cancer cells as a model. RON was almost exclusively expressed at variable levels in normal epithelial cells from the digestive track, lung, kidney, pancreas, liver, breast, bladder, skin, and others. Among 15 types of cancer studied, RON was overexpressed in significant numbers in cancers derived from breast (56%), colon (51%), lung (48), thyroid (42%), skin (37%), bladder (36%), and pancreas (33%). In contrast, limited RON overexpression was observed in cancers from stomach, kidney, brain, liver, ovary, and prostate. Detailed analysis of thyroid tissues showed that RON was hardly detected in normal thyroid cells, moderately expressed in adenoma samples, but overexpressed in about half of papillary and follicular cancer specimens. Overexpression correlated with advanced clinical stage and was associated with lymph node metastasis. In cultured thyroid cancer cells, RON was highly expressed, with constitutive phosphorylation. Activation of RON increased cell growth and migration via the MAP kinase and AKT pathways. Silencing RON expression significantly prevented cell growth and increased cell apoptotic death. These findings show that RON overexpression occurs in a particular group of epithelial cancers. The requirement for RON in sustaining tumourigenic phenotypes suggests that it is a potential target for therapeutic intervention.
Wang
M-H
MH
Laboratory of Cancer Biology and Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China 310003. minghai.wang@ttuhsc.edu
Lee
W
W
Luo
Y-L
YL
Weis
M T
MT
Yao
H-P
HP
D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis / Q000379:methods; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases