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¹ Department of Internal Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois; ² AVI BioPharma, Corvallis, Oregon; ³ Department of Pathology, University of Chicago Hospitals, Chicago, Illinois; and ⁴ Biomedical Engineering Department, Northwestern University, Evanston, Illinois

Requests for reprints: Hemant K. Roy, Department of Internal Medicine, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201. Phone: 847-570-7683; Fax: 847-570-8011. E-mail: h-roy{at}northwestern.edu

Objectives: Emerging evidence implicates the SNAIL family of transcriptional repressors in cancer development; however, the role of SNAIL in colorectal cancer has not been established. To investigate the importance of SNAIL in colorectal carcinogenesis, we examined the phenotypic and cellular consequences of SNAIL down-regulation in the MIN mouse. Methods: Twenty-eight male MIN mice were randomized to treatment with an antisense phosphorodiamidate morpholino oligomer (AS-PMO) to SNAIL, saline, or a scrambled sequence control for 6 weeks. Tumors were scored and the molecular/cellular effects of anti-SNAIL treatment were evaluated through immunohistochemical analysis of the uninvolved intestinal mucosa for SNAIL and E-cadherin levels along with rates of apoptosis and proliferation. Furthermore, microarchitectural alterations were determined through measurement of fractal dimension. Results: In the uninvolved mucosa, SNAIL AS-PMO treatment moderately decreased SNAIL protein when compared with saline-treated animals (immunohistochemistry scores 3.0 ± 0.8 versus 2.1 ± 0.6, respectively; P = 0.01) with a concomitant increase in E-cadherin expression (1.8 ± 0.6 versus 2.4 ± 0.5; P < 0.05). Anti-SNAIL PMO, but not scramble control, resulted in a significant decrease in both total tumor number and incidence of tumors >2 mm (22% and 54%, respectively; P < 0.05). Furthermore, this was accompanied by an increased apoptosis rate (2-fold), decreased proliferation (3-fold), and normalization of the fractal dimension in the uninvolved intestinal mucosa. Conclusions: We show, for the first time, that SNAIL overexpression is important in intestinal tumorigenesis. While this PMO regimen afforded modest SNAIL suppression and hence tumor reduction, this provides compelling evidence for the role of SNAIL overexpression in colonic neoplasia.

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Note: Presented in part in abstract form at the 105th Digestive Disease Week Meetings, May 16–19, 2004, New Orleans, LA.

Received 4/21/04; revised 6/18/04; accepted 6/30/04.

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