Bile acid: a potential inducer of colon cancer stem cells.

Lulu Farhana,Hamidah Mahmud,Adhip P N Majumdar,Yingjie Yu,Kathren Shango,Timothy Hadden,Pratima Nangia-Makker,Evan Arbit,Sarah Sarkar

doi:10.1186/s13287-016-0439-4

Lulu Farhana, Hamidah Mahmud + Show 7 more

Open Access

https://doi.org/10.1186/s13287-016-0439-4

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Abstract

BackgroundAlthough the unconjugated secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood. We hypothesize that the cytotoxic bile acids may promote stemness in colonic epithelial cells leading to generation of cancer stem cells (CSCs) that play a role in the development and progression of colon cancer.MethodsNormal human colonic epithelial cells (HCoEpiC) were used to study bile acid DCA/LCA-mediated induction of CSCs. The expression of CSC markers was measured by real-time qPCR. Flow cytometry was used to isolate CSCs. T-cell factor/lymphoid-enhancing factor (TCF/LEF) luciferase assay was employed to examine the transcriptional activity of β-catenin. Downregulation of muscarinic 3 receptor (M3R) was achieved through transfection of corresponding siRNA.ResultsWe found DCA/LCA to induce CSCs in normal human colonic epithelial cells, as evidenced by the increased proportion of CSCs, elevated levels of several CSC markers, as well as a number of epithelial–mesenchymal transition markers together with increased colonosphere formation, drug exclusion, ABCB1 and ABCG2 expression, and induction of M3R, p-EGFR, matrix metallopeptidases, and c-Myc. Inhibition of M3R signaling greatly suppressed DCA/LCA induction of the CSC marker ALDHA1 and also c-Myc mRNA expression as well as transcriptional activation of TCF/LEF.ConclusionsOur results suggest that bile acids, specifically DCA and LCA, induce cancer stemness in colonic epithelial cells by modulating M3R and Wnt/β-catenin signaling and thus could be considered promoters of colon cancer.

Highlights

The unconjugated secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood
In the first set of experiments, we examined the changes in expression of several cancer stem cells (CSCs) markers as well as the proportion of CSCs in human colonic epithelial cells (HCoEpiC) following exposure to DCA or LCA for 72 h
The proportion of CD44positive and CD166-positive populations was found to be markedly higher in DCA-treated or LCA-treated cells, compared with the corresponding vehicle-treated control (Fig. 1d). These observations suggest that DCA and LCA can induce CSCs in colonic epithelial cells. To further investigate this issue, we examined the ability of DCA and LCA to stimulate spheroid formation by HCoEpiC, a property common to both normal and CSCs

Summary

Introduction

The unconjugated secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood. It has long been known that certain secondary bile acids, secreted into the intestinal lumen and involved in fat absorption, can promote colon carcinogenesis [2,3,4]. Levels of bile acids are known to Epidemiological studies have revealed that the incidence of colorectal cancer (CRC) among populations migrating from low-incidence to high incidence countries changes rapidly. The incidence of CRC reached its highest level in people migrating from Japan to Hawaii [9]. This has been thought to be largely due to changes in diet.

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