Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential.
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 RONdelta165, RONdelta160, and RONdelta155 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 beta chain. Functional studies showed that expression of RONdelta160 or RONdelta155 in Martin-Darby canine kidney cells resulted in increased cell dissociation (scatter-like activity). RON variants, RONdelta160 and RONdelta155, also exerted the ability to induce multiple focus formation and sustain anchorage-independent growth of transfected NIH3T3 cells. Moreover, NIH3T3 cells expressing RONdelta160 or RONdelta155 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.
Zhou
Yong-Qing
YQ
Division of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
He
Chao
C
Chen
Yi-Qing
YQ
Wang
Dong
D
Wang
Ming-Hai
MH
D016475:3T3 Cells / Q000473:pathology; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015197:Carcinogenicity Tests; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011956:Receptors, Cell Surface; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases