Interplay between APC and ALDH1B1 in a newly developed mouse model of colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Recently, we demonstrated that aldehyde dehydrogenase 1B1 (ALDH1B1) knockdown dramatically reduced colon tumor growth in a mouse xenograft model. The purpose of the present preliminary study is to examine the effect of loss of ALDH1B1 in CRC development in an inducible colon-specific Apc mouse model.

Methods: Apc^W/FCdx2^ERT2-Cre mice develop uni-allelic inactivation of Apc specifically in colon epithelial cells following tamoxifen treatment. Aldh1b1^-/- KO mice were crossed with Apc^W/FCdx2^ERT2-Cre mice. Six-month-old male Apc^W/FCdx2^ERT2-Cre/Aldh1b1^-/-, and Apc^W/FCdx2^ERT2-Cre/Aldh1b1^+/+ mice were treated with tamoxifen (50 mg/kg, i.p.) for three consecutive days. Apc^W/F/Aldh1b1^-/- and Apc^W/F/Aldh1b1^+/+ mice were treated with corn oil (i.e., tamoxifen vehicle control) for three consecutive days. Eighteen days later, mice were sacrificed and their colons examined microscopically, macroscopically and histologically for the presence of adenoma.

Results: All Apc^W/FCdx2^ERT2-Cre/Aldh1b1^+/+ and Apc^W/FCdx2^ERT2-Cre/Aldh1b1^-/- mice treated with tamoxifen developed colorectal adenoma. The Apc^W/FCdx2^ERT2-Cre/Aldh1b1^-/- mice showed a significant decrease in the total volume of all ileal and colonic adenomas, and decreased incidence of large colonic adenoma compared to Apc^W/FCdx2^ERT2-Cre/Aldh1b1^+/+ mice. Immunohistochemical analysis of p53 and β-catenin showed a trend toward decreased expression score in colonic adenomas of Apc^W/FCdx2^ERT2-Cre/Aldh1b1^-/- mice.

Conclusion: The present preliminary study suggests that deletion of ALDH1B1 may protect against the full development of colorectal cancer. Further mechanistic studies are required to elucidate how ALDH1B1 contributes for colorectal cancer.

Keywords: Adenomatous polyposis coli; Aldehyde dehydrogenase 1B1; Beta-catenin; Colorectal cancer; Mouse models; p53.