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10.1245/ASO.2004.03.056
Annals of Surgical Oncology 11:192-196 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Deleted in Oral Cancer-1 Expression Upregulates Proapoptosis Elements in Microsatellite-Unstable Human Colorectal Cancer

Tara Sotsky Kent, MD, Ziqiang Yuan, MD, Agnes Miller, BA and Thomas K. Weber, MD, FACS

From the Departments of Surgery (TSK, TKW) and Molecular Genetics (TKW), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York; and Departments of Molecular Genetics (ZY) and Surgery (AM), Albert Einstein College of Medicine, Bronx, New York.

Correspondence: Address correspondence and reprint requests to: Thomas K. Weber, MD, FACS, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 1219, Bronx, NY 10467; Fax: 718-430-2773; E-mail: tweber{at}aecom.yu.edu

Background: We previously reported differential expression of the growth suppressor, deleted in oral cancer-1 (DOC-1), in microsatellite-unstable (MSI+) versus microsatellite-stable colorectal cancer (CRC) cell lines. MSI+ CRC cell lines demonstrated decreased DOC-1 expression and decreased apoptosis. Transfection of wild-type DOC-1 into an MSI+ cell line (SW48) resulted in increased apoptosis. We undertook our current experiment to identify specific elements modulated by DOC-1 expression that result in increased apoptosis.

Methods: SW48 is an MSI+ CRC cell line that does not constitutively express DOC-1. SW48 was suspended in culture medium and incubated to 60% confluence. Half the plates were transfected with cytomegalovirus (CMV)-DOC-1. At 30 hours, RNA and protein were isolated with Trizol. Complementary DNA microarray was performed to compare SW48CMV-DOC-1 with SW48, which lacks DOC-1. Signal intensity was analyzed by GenePix Pro 3.0 software. Expression ratios <=.67 and >=1.5 were considered significant. Poor-quality spots were flagged and excluded from analysis. Real-time polymerase chain reaction was performed to determine DOC-1 levels in both cell lines.

Results: Successful transfection of DOC-1 was confirmed by real-time polymerase chain reaction and by Western blot. Microarray revealed significant differential expression of DOC-1, as expected. Increased DOC-1 expression in SW48CMV-DOC-1 was associated with significantly increased expression of proapoptosis components of the caspase cascade (CASP7, CASP9) and bcl2/bax pathway (BNIP3, BNIP3L, BID).

Conclusions: DOC-1 expression promotes apoptosis by upregulation of specific elements of the caspase cascade and bcl2/bax pathways. DOC-1 therefore deserves further study as a candidate for the therapeutic modulation of apoptosis in MSI+ CRC.

Key Words: DOC-1 • Colorectal carcinoma • Apoptosis • Microsatellite unstable




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