Down-regulation of SNAIL suppresses MIN mouse tumorigenesis: Modulation of apoptosis, proliferation, and fractal dimension

Hemant K. Roy*, Patrick Iversen, John Hart, Yang Liu, Jennifer L. Koetsier, Young Kim, Dhanajay P. Kunte, Madhavi Madugula, Vadim Backman, Ramesh K. Wali

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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 regi men afforded modest SNAIL suppression and hence tumor reduction, this provides compelling evidence for the role of SNAIL overexpression in colonic neoplasia.

Original languageEnglish (US)
Pages (from-to)1159-1165
Number of pages7
JournalMolecular cancer therapeutics
Volume3
Issue number9
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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