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

Oncogene volume 22, pages 7950–7957 (2003)Cite this article

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 (T2–4 versus T1), 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.

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Acknowledgements

We thank Chiang-Ching Huang, Kerby A Shedden, Jeremy MG Taylor, and Sharon LR Kardia for their helpful discussions. This work was supported by NCI Grant U19 CA-85953.

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Author notes

  1. Charles T Miller, Guoan Chen and Tarek G Gharib: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, University of Michigan Medical School, Ann Arbor, 48109, MI, USA

    Charles T Miller, Guoan Chen, Tarek G Gharib, John Yee, Mark B Orringer & David G Beer

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA

    Dafydd G Thomas & Thomas J Giordano

  3. Department of Pediatrics, University of Michigan Medical School, Ann Arbor, 48109, MI, USA

    Hong Wang, David E Misek & Samir M Hanash

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  1. Charles T Miller
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Correspondence to David G Beer.

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Miller, C., Chen, G., Gharib, T. et al. Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas. Oncogene 22, 7950–7957 (2003). https://doi.org/10.1038/sj.onc.1206529

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