Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas.

Abstract

The C-CRK gene, cellular homolog of the avian v-crk oncogene, encodes two alternatively spliced adaptor signaling proteins, CRKI (28 kDa) and CRKII (40 kDa). Both CRKI and CRKII have been shown to activate kinase signaling and anchorage-independent growth in vitro and CRKI transformed cells readily form tumors in nude mice. Affymetrix oligonucleotide arrays were used to analyse 86 lung adenocarcinomas and 10 uninvolved lung tissues. C-CRK mRNA expression was increased in more advanced (stage III versus stage I), larger (T(2-4) versus T(1)), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (P=0.00034). An overlapping series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung specimens were measured for quantitative differences in CRKI and CRKII protein levels using 2-D PAGE. CRK protein spots were identified using mass spectrometry and 2-D Western blotting. A significant increase in levels of the CRKI oncoprotein and the phosphorylated isoform of CRKII was observed in tumors (P<0.05). No difference in protein level was evident between stages. Concordant with mRNA expression, CRKI and CRKII were increased in poorly differentiated tumors (P<0.05). CRK immunohistochemical analysis of tumor tissue arrays using the same tumor series also demonstrated increased abundance of nuclear and cytoplasmic CRK in more proliferative tumors (P<0.05). This study provides the first quantitative analysis of discrete CRKI and CRKII protein isoforms in human lung tumors and provides evidence that the C-CRK proto-oncogene may foment a more aggressive phenotype in lung cancers.

• Authors: Charles T Miller, Guoan Chen, Tarek G Gharib, Hong Wang, Dafydd G Thomas, David E Misek, Thomas J Giordano, John Yee, Mark B Orringer, Samir M Hanash, David G Beer
• Journal: Oncogene (Oncogene) Vol. 22 Issue 39 Pg. 7950-7 (Sep 11 2003) ISSN: 0950-9232 [Print] England
• PMID: 12970743 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• MAS1 protein, human
• Protein Isoforms
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-crk
• RNA, Messenger

Topics

• Adenocarcinoma (genetics, pathology)
• Cell Division (genetics)
• Electrophoresis, Gel, Two-Dimensional
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry (methods)
• Lung Neoplasms (genetics, pathology)
• Neoplasm Invasiveness
• Phenotype
• Protein Isoforms (genetics)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-crk
• RNA, Messenger (metabolism)
• Tumor Cells, Cultured