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Journal of Cancer Prevention

Original Article

J Cancer Prev 2021; 26(1): 32-40

Published online March 30, 2021

https://doi.org/10.15430/JCP.2021.26.1.32

© Korean Society of Cancer Prevention

Dysregulated Free Fatty Acid Receptor 2 Exacerbates Colonic Adenoma Formation in ApcMin/+ Mice: Relation to Metabolism and Gut Microbiota Composition

Yi-Wen Huang1 ,*, Chien-Wei Lin2 ,*, Pan Pan3 ,*, Carla Elena Echeveste3 , Athena Dong3 , Kiyoko Oshima4 , Martha Yearsley5 , Jianhua Yu6 ,**, Li-Shu Wang3 ,**

1Department of Obstetrics & Gynecology, 2Division of Biostatistics, 3Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 4Department of Pathology, Johns Hopkins University, Baltimore, MD, 5Department of Pathology, The Ohio State University, Columbus, OH, 6Department of Hematology and Hematopoietic Cell Transplantation, Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA, USA

Correspondence to :
Li-Shu Wang, E-mail: liswang@mcw.edu, https://orcid.org/0000-0002-6500-6943
Jianhua Yu, E-mail: jiayu@coh.org, https://orcid.org/0000-0002-0326-3223
*These authors contributed equally to this work as co-first authors.
**These authors contributed equally to this work as co-correspondence authors.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (ApcMin/+). Ffar2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, ApcMin/+, and ApcMin/+-Ffar2-/- mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the ApcMin/+-Ffar2-/- mice compared to the ApcMin/+ mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, longchain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that Ffar2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.

Keywords: Ffar2, ApcMin/+, Colorectal cancer, Metabolomics, Gut microbiota

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