The secondary bile acid, deoxycholate accelerates intestinal adenoma–adenocarcinoma sequence in Apc min/+ mice through enhancing Wnt signaling

Abstract

Colorectal cancer is one of the leading causes of cancer deaths. It correlates to a high fat diet, which causes an increase of the secondary bile acids including deoxycholate (DOC) in the intestine. We aimed to determine the effects of DOC on intestinal carcinogenesis in Apc (min/+) mice, a model of spontaneous intestinal adenomas. Four-week old Apc (min/+) mice were treated with 0.2 % DOC in drinking water for 12 weeks. The number and size of tumors were measured, and tissue sections were prepared for the evaluation of intestinal carcinogenesis, cell proliferation, and apoptosis. The activation of Wnt signaling was detected in the intestinal tumor cells of the Apc (min/+) mice, and also in the human colon samples. DOC increased the number of intestine tumors by 165.1 % compared with that in untreated Apc (min/+) mice mainly in the middle and distal segments of the small intestine and colon. The numbers of all sizes of tumors in the small intestine were increased. Intestinal carcinogenesis was confirmed in 75 % mice in DOC treated-Apc (min/+) mice compared with 0 % in untreated mice. This was accompanied by promoting tumor cell proliferation and decreasing apoptosis, and increasing the percentage of β-catenin positive cells and its nuclear expression in intestinal tumor cells of Apc (min/+) mice, and also up-regulating the expression of cyclin D1. In addition, the activation of Wnt signaling also played in modulating human colon carcinogenesis. Our studies suggest that DOC enhances the multiplicity of intestinal tumor, and accelerates intestinal adenoma-adenocarcinoma sequence in Apc (min/+) mice mediated by stimulating tumor cell proliferation and decreasing apoptosis through enhancing Wnt signaling.

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

“…While BAs have been shown to interact with the EGFR pathway in numerous tissues, including the colon (10,44), liver (63), bile ducts (74,75), stomach (73), and esophagus (3), discrepancies in the literature exist here as well. For example, in Caco-2 cells, DCA was found to inhibit barrier function via EGFR phosphorylation (62), although EGF administration is typically associated with improved barrier function (6, 7).…”

Characterization of Colorectal Cancer Development in Apc min/+ Mice

“…In this chapter, we will describe techniques for studying colon cancer development in Apc min/+ mice on a C57BL/6J (B6) genetic background, focusing on Dextran Sulfate Sodium-induced (DSS) [14–17], high fat diet-induced [18–20], and bile acid supplementation [21, 22] as environmentally modifiable models of colorectal cancer. This chapter also includes protocols describing extraction and purification of DSS-contaminated RNA [23], as well as sampling, harvesting, and tissue processing.…”

Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis

“…Intestinal tumors were categorized as small (<1 mm), medium (1‐2 mm), or large (>2 mm). Swiss rolled distal small intestine and colon tissues were fixed in 10% buffered formalin . The tissue sections were used for hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining.…”

“…Multiple intestinal neoplasia ( Apc min/+ ) mice spontaneously develop multiple tumors in the intestine and are an established model for studying intestinal carcinogenesis. In our previous work, we aimed to determine the effects of DCA on intestinal carcinogenesis in Apc min/+ mice and found that DCA accelerates the intestinal adenoma‐adenocarcinoma sequence . Next, we investigated the effect of DCA on the induction of intestinal dysbiosis and its roles in intestinal carcinogenesis and demonstrated that DCA‐induced changes to the microbial community promoted intestinal carcinogenesis .…”