This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wen, Y. Articles by Notterman, D. Search for Related Content PubMed PubMed Citation Articles by Wen, Y. Articles by Notterman, D.

GRO Is Highly Expressed in Adenocarcinoma of the Colon and Down-Regulates Fibulin-1

Authors' Affiliations: ¹ Robert Wood Johnson Medical School and Cancer Institute of New Jersey, New Brunswick, New Jersey; ² Princeton University, Princeton, New Jersey; ³ Weil Medical College of Cornell University; and ⁴ Memorial-Sloan Kettering Cancer Center, New York, New York

Requests for reprints: Daniel A. Notterman, Departments of Pediatrics and Molecular Genetics, Robert Wood Johnson Medical School, 125 Patterson Street, MEB 306, New Brunswick, NJ 08903. Phone: 732-235-7900; Fax: 732-235-6102; E-mail: d.notterman{at}umdnj.edu.

Purpose: The growth-related oncogene (GRO) is a secreted interleukin-like molecule that interacts with the CXCR2 G-protein–coupled receptor. We found that the mRNA and protein products of GRO are more highly expressed in neoplastic than normal colon epithelium, and we studied potential mechanisms by which GRO may contribute to tumor initiation or growth.

Experimental Design: Cell lines that constitutively overexpress GRO were tested for growth rate, focus formation, and tumor formation in a xenograft model. GRO expression was determined by Affymetrix GeneChip (241 microdissected colon samples), real-time PCR (n = 32), and immunohistochemistry. Primary colon cancer samples were also employed to determine copy number changes and loss of heterozygosity related to the GRO and fibulin-1 genes.

Results: In cell cultures, GRO transfection transformed NIH 3T3 cells, whereas inhibition of GRO by inhibitory RNA was associated with apoptosis, decreased growth rate, and marked up-regulation of the matrix protein fibulin-1. Forced expression of GRO was associated with decreased expression of fibulin-1. Expression of GRO mRNA was higher in primary adenocarcinomas (n = 132), adenomas (n = 32), and metastases (n = 52) than in normal colon epithelium (P < 0.001). These results were confirmed by real-time PCR and by immunohistochemistry. Samples of primary and metastatic colon cancer showed underexpression of fibulin-1 when compared with normal samples. There were no consistent changes in gene copy number of GRO or fibulin-1, implying a transcriptional basis for these findings.

Conclusion: Elevated expression of GRO is frequent in adenocarcinoma of the colon and is associated with down-regulation of the matrix protein fibulin-1 in experimental models and in clinical samples. GRO overexpression abrogates contact inhibition in cell culture models, whereas inhibition of GRO expression is associated with apoptosis. Importantly, coexpression of fibulin-1 with GRO abrogates key aspects of the transformed phenotype, including tumor formation in a murine xenograft model. Targeting GRO proteins may provide new opportunities for treatment of colon cancer.

This article has been cited by other articles:

				M. D. Bacolod, G. S. Schemmann, S. Wang, R. Shattock, S. F. Giardina, Z. Zeng, J. Shia, R. F. Stengel, N. Gerry, J. Hoh, et al. The Signatures of Autozygosity among Patients with Colorectal Cancer Cancer Res., April 15, 2008; 68(8): 2610 - 2621. [Abstract] [Full Text] [PDF]