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Clinical Cancer Research Vol. 5, 1805-1815, July 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Paradoxical Increase in Retinoblastoma Protein in Colorectal Carcinomas May Protect Cells from Apoptosis1

Hirofumi Yamamoto, Jae-Won Soh, Takushi Monden, Micheal G. Klein, Li Ming Zhang, Haim Shirin, Nadir Arber, Naohiro Tomita, Ira Schieren, C. A. Stein and I. Bernard Weinstein2

Herbert Irving Comprehensive Cancer Center [H. Y., J-W. S., M. G. K., H. S., C. A. S., I. B. W.], Center for Neurobiology and Behavior [I. S.], Department of Medicine [L. M. Z., C. A. S., I. B. W.], and Department of Pharmacology [C. A. S.], Columbia University, College of Physicians and Surgeons, New York, New York 10032; Department of Surgery II, Osaka University Medical School, Osaka, 565-0871, Japan [H. Y., T. M., N. T.]; and Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, 64239, Israel [N. A.]

The retinoblastoma (Rb) gene is inactivated in a variety of human cancers, but in colorectal carcinomas there is frequently increased expression of this gene. This is paradoxical in view of the known role of Rb as a tumor suppressor gene. In the present study, we compared the levels of expression of the Rb protein (pRb) in normal human colorectal mucosa, adenomatous polyps, and carcinomas by immunohistochemistry. In vitro studies were also done to examine the phenotypic effects of an antisense oligo-deoxynucleotide (AS-Rb) targeted to Rb mRNA in the HCT116 colon carcinoma cell line that expresses a relatively high level of pRb. The incidence of pRb-positive cells was increased during multistage colorectal carcinogenesis. In vitro treatment of HCT116 cells with AS-Rb decreased the level of pRb by about 70% and also decreased the levels of the cyclin D1 protein and cyclin D1-associated kinase activity. AS-Rb inhibited growth of HCT116 cells and induced apoptosis. Reporter assays indicated about a 17-fold increase in E2F activity. These findings suggest that the increased expression of pRb in colorectal carcinoma cells may provide a homeostatic mechanism that protects them from growth inhibition and apoptosis, perhaps by counterbalancing potentially toxic effects of excessive E2F activity.




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Copyright © 1999 by the American Association for Cancer Research.