These authors contributed equally to this work.
Integration of genomic analysis and in vivo transfection to identify sprouty 2 as a candidate tumor suppressor in liver cancer†
Article first published online: 19 DEC 2007
Copyright © 2008 American Association for the Study of Liver Diseases
Volume 47, Issue 4, pages 1200–1210, April 2008
How to Cite
Lee, S. A., Ho, C., Roy, R., Kosinski, C., Patil, M. A., Tward, A. D., Fridlyand, J. and Chen, X. (2008), Integration of genomic analysis and in vivo transfection to identify sprouty 2 as a candidate tumor suppressor in liver cancer. Hepatology, 47: 1200–1210. doi: 10.1002/hep.22169
Potential conflict of interest: Nothing to report.
- Issue published online: 25 MAR 2008
- Article first published online: 19 DEC 2007
- Accepted manuscript online: 19 DEC 2007 12:00AM EST
- Manuscript Accepted: 4 DEC 2007
- Manuscript Received: 12 OCT 2007
- National Institutes of Health K01. Grant Number: K01CA096774
- University of California San Francisco Liver Center Pilot/Feasibility grant award. Grant Number: P30DK026743
Hepatocellular carcinoma (HCC) is 1 of the leading causes of cancer-related deaths worldwide, yet the molecular genetics underlying this malignancy are still poorly understood. In our study, we applied statistical methods to correlate human HCC gene expression data obtained from complementary DNA (cDNA) microarrays and corresponding DNA copy number variation data obtained from array-based comparative genomic hybridization. We have thus identified 76 genes that are up-regulated and show frequent DNA copy number gain, and 37 genes that are down-regulated and show frequent DNA copy loss in human HCC samples. Among these down-regulated genes is Sprouty2 (Spry2), a known inhibitor of receptor tyrosine kinases. We investigated the potential role of Spry2 in HCC by expressing dominant negative Spry2 (Spry2Y55F) and activated β-catenin (ΔN90-β-catenin) in the mouse liver through hydrodynamic injection and sleeping beauty–mediated somatic integration. When stably expressed in mouse hepatocytes, Spry2Y55F cooperates with ΔN90-β-catenin to confer a neoplastic phenotype in mice. Tumor cells show high levels of expression of phospho-extracellular signal-regulated kinase (ERK), as well as deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. Conclusion: We identified a set of candidate oncogenes and tumor suppressor genes for human HCC. Our study provides evidence that inhibition of Spry activity cooperates with other oncogenes to promote liver cancer in mouse models, and Spry2 may function as a candidate tumor suppressor for HCC development in vivo. In addition, we demonstrate that the integration of genomic analysis and in vivo transfection is a powerful tool to identify genes that are important during hepatic carcinogenesis. (HEPATOLOGY 2008.)