CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis.

BACKGROUND & AIMS The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines. METHODS Gene expression array analysis ([RG-U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase-2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas). Human cancer cell lines were tested for their response to anti-CD24 monoclonal antibodies. RESULTS A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6%). Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose- and time-dependent manners. These results were repetitive for 3 different antibodies. CONCLUSIONS CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy.

[1]  H. Blum,et al.  Molecular pathogenesis of colorectal cancer , 2005, Cancer.

[2]  J. Morrow,et al.  Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. , 1997, The Journal of clinical investigation.

[3]  D. Figarella-Branger,et al.  CD24, a glycosylphosphatidylinositol-anchored molecule, is transiently expressed during the development of human central nervous system and is a marker of human neural cell lineage tumors , 1996, Acta Neuropathologica.

[4]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[5]  Thomas D. Wu,et al.  Analysing gene expression data from DNA microarrays to identify candidate genes , 2001, The Journal of pathology.

[6]  N. Kiyokawa,et al.  CD24 Induces Apoptosis in Human B Cells Via the Glycolipid-Enriched Membrane Domains/Rafts-Mediated Signaling System1 , 2001, The Journal of Immunology.

[7]  P. Altevogt,et al.  The CD24/P-selectin binding pathway initiates lung arrest of human A125 adenocarcinoma cells. , 2000, Cancer research.

[8]  W. Weichert,et al.  Cytoplasmic CD24 Expression in Colorectal Cancer Independently Correlates with Shortened Patient Survival , 2005, Clinical Cancer Research.

[9]  R. Stahel,et al.  Association of CD24 with the kinase c-fgr in a small cell lung cancer cell line and with the kinase lyn in an erythroleukemia cell line. , 1996, Biochemical and biophysical research communications.

[10]  G. Piazza,et al.  A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat enterocytes. , 1997, Gastroenterology.

[11]  D. Lockhart,et al.  Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Z. Halpern,et al.  Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus , 2001, Oncogene.

[13]  C. Pilarsky,et al.  Expression of CD24 in Adenocarcinomas of the Pancreas Correlates with Higher Tumor Grades , 2004, Pancreatology.

[14]  B. Vogelstein,et al.  Prevalence of ras gene mutations in human colorectal cancers , 1987, Nature.

[15]  N. Arber,et al.  Non-steroidal anti-inflammatory drugs and selective apoptotic anti-neoplastic drugs in the prevention of colorectal cancer: the role of super aspirins. , 2000, The Israel Medical Association journal : IMAJ.

[16]  D. Haller,et al.  Therapy for early-stage colorectal cancer. , 1999, Oncology.

[17]  R. Coffey,et al.  Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. , 1994, Gastroenterology.

[18]  K. Seibert,et al.  Advances in Brief Evaluation of Cyclooxygenase-2 Inhibitor for Potential Chemopreventive Properties in Colon Carcinogenesis ' , 2006 .

[19]  Peter Altevogt,et al.  CD24 affects CXCR4 function in pre-B lymphocytes and breast carcinoma cells , 2006, Journal of Cell Science.

[20]  R. DuBois,et al.  Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. , 1996, Gastroenterology clinics of North America.

[21]  Han-Woong Lee,et al.  TCR-Independent and Caspase-Independent Apoptosis of Murine Thymocytes by CD24 Cross-Linking1 , 2004, The Journal of Immunology.

[22]  I. Weinstein,et al.  Increased expression of cyclin D1 and the Rb tumor suppressor gene in c-K-ras transformed rat enterocytes. , 1996, Oncogene.

[23]  P. Altevogt,et al.  CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. , 1997, Blood.

[24]  Robert Riddell,et al.  Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. , 2005, The New England journal of medicine.

[25]  P. Altevogt,et al.  Differential, LFA-1-sensitive effects of antibodies to nectadrin, the heat-stable antigen, on B lymphoblast aggregation and signal transduction. , 1994, Biochemical and biophysical research communications.

[26]  E. Hawk,et al.  Development of COX Inhibitors in Cancer Prevention and Therapy , 2003, American journal of clinical oncology.

[27]  S Jothy,et al.  Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. , 1995, Cancer research.

[28]  N. Arber,et al.  Celecoxib But Not Rofecoxib Inhibits the Growth of Transformed Cells in Vitro , 2004, Clinical Cancer Research.

[29]  L. Distel,et al.  CD24 promotes invasion of glioma cells in vivo. , 1999, Journal of neuropathology and experimental neurology.

[30]  Y. Shin,et al.  Cytoplasmic CD24 expression in advanced ovarian serous borderline tumors. , 2005, Gynecologic oncology.

[31]  Marc A Pfeffer,et al.  Cardiovascular Risk Associated With Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention , 2005, The New England journal of medicine.

[32]  Hideki Nakajima,et al.  Pre-B Cell Antigen Receptor-Mediated Signal Inhibits CD24-Induced Apoptosis in Human Pre-B Cells1 , 2003, The Journal of Immunology.

[33]  H. Hsu,et al.  Cloning and expression of CD24 gene in human hepatocellular carcinoma: a potential early tumor marker gene correlates with p53 mutation and tumor differentiation. , 1995, Cancer research.

[34]  G. Kristiansen,et al.  Tumour Biological Aspects of CD24, A Mucin-Like Adhesion Molecule , 2003, Journal of Molecular Histology.

[35]  O. Margalit,et al.  Overexpression of a set of genes, including WISP-1, common to pulmonary metastases of both mouse D122 Lewis lung carcinoma and B16-F10.9 melanoma cell lines , 2003, British Journal of Cancer.

[36]  R. DuBois,et al.  Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2 , 1995, Cell.

[37]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[38]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[39]  S. Loening,et al.  CD24 expression is a significant predictor of PSA relapse and poor prognosis in low grade or organ confined prostate cancer , 2004, The Prostate.

[40]  C. Pilarsky,et al.  CD24 expression is a new prognostic marker in breast cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.