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Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM

BACKGROUND: Our previous study showed that fucosyltransferase 2 (Fut2) deficiency is closely related to colitis. Colitis increases the risk for the development of colorectal cancer (CRC). This study aimed to investigate the effect and underlying mechanism of action of Fut2 in CRC. METHODS: Intestina...

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Autores principales: Wang, Weijun, Tang, Xuelian, Duan, Caihan, Tian, Shuxin, Han, Chaoqun, Qian, Wei, Jiang, Xin, Hou, Xiaohua, Lin, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899399/
https://www.ncbi.nlm.nih.gov/pubmed/36739428
http://dx.doi.org/10.1186/s12967-023-03906-0
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author Wang, Weijun
Tang, Xuelian
Duan, Caihan
Tian, Shuxin
Han, Chaoqun
Qian, Wei
Jiang, Xin
Hou, Xiaohua
Lin, Rong
author_facet Wang, Weijun
Tang, Xuelian
Duan, Caihan
Tian, Shuxin
Han, Chaoqun
Qian, Wei
Jiang, Xin
Hou, Xiaohua
Lin, Rong
author_sort Wang, Weijun
collection PubMed
description BACKGROUND: Our previous study showed that fucosyltransferase 2 (Fut2) deficiency is closely related to colitis. Colitis increases the risk for the development of colorectal cancer (CRC). This study aimed to investigate the effect and underlying mechanism of action of Fut2 in CRC. METHODS: Intestinal epithelium-specific Fut2 knockout (Fut2(△IEC)) mice were used in this study. CRC was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Immunofluorescence was used to examine the fucosylation levels. Proteomics and N-glycoproteomics analyses, Ulex Europaeus Agglutinin I (UEA-I) affinity chromatography, immunoprecipitation, and rescue assay were used to investigate the mechanism of Fut2 in CRC. RESULTS: The expression of Fut2 and α-1,2-fucosylation was lower in colorectal tumor tissues than in the adjacent normal tissues of AOM/DSS-induced CRC mice. More colorectal tumors were detected in Fut2(△IEC) mice than in control mice, and significant downregulation of melanoma cell adhesion molecule (MCAM) fucosylation was detected in the colorectal tumor tissues of Fut2(△IEC) mice. Overexpression of Fut2 inhibited cell proliferation, invasion and tumor metastasis in vivo and in vitro in SW480 and HCT116 cells. Moreover, fucosylation of MCAM may be a mediator of Fut2 in CRC. Peracetylated 2-F-Fuc, a fucosyltransferase inhibitor, repressed fucosylation modification of MCAM and reversed the inhibitory effects of Fut2 overexpression on SW480 cell proliferation, migration, and invasion. Our results indicate that Fut2 deficiency in the intestinal epithelium promotes CRC by downregulating the fucosylation of MCAM. CONCLUSIONS: The regulation of fucosylation may be an potential therapy for CRC, especially in patients with Fut2 gene defects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-03906-0.
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spelling pubmed-98993992023-02-06 Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM Wang, Weijun Tang, Xuelian Duan, Caihan Tian, Shuxin Han, Chaoqun Qian, Wei Jiang, Xin Hou, Xiaohua Lin, Rong J Transl Med Research BACKGROUND: Our previous study showed that fucosyltransferase 2 (Fut2) deficiency is closely related to colitis. Colitis increases the risk for the development of colorectal cancer (CRC). This study aimed to investigate the effect and underlying mechanism of action of Fut2 in CRC. METHODS: Intestinal epithelium-specific Fut2 knockout (Fut2(△IEC)) mice were used in this study. CRC was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS). Immunofluorescence was used to examine the fucosylation levels. Proteomics and N-glycoproteomics analyses, Ulex Europaeus Agglutinin I (UEA-I) affinity chromatography, immunoprecipitation, and rescue assay were used to investigate the mechanism of Fut2 in CRC. RESULTS: The expression of Fut2 and α-1,2-fucosylation was lower in colorectal tumor tissues than in the adjacent normal tissues of AOM/DSS-induced CRC mice. More colorectal tumors were detected in Fut2(△IEC) mice than in control mice, and significant downregulation of melanoma cell adhesion molecule (MCAM) fucosylation was detected in the colorectal tumor tissues of Fut2(△IEC) mice. Overexpression of Fut2 inhibited cell proliferation, invasion and tumor metastasis in vivo and in vitro in SW480 and HCT116 cells. Moreover, fucosylation of MCAM may be a mediator of Fut2 in CRC. Peracetylated 2-F-Fuc, a fucosyltransferase inhibitor, repressed fucosylation modification of MCAM and reversed the inhibitory effects of Fut2 overexpression on SW480 cell proliferation, migration, and invasion. Our results indicate that Fut2 deficiency in the intestinal epithelium promotes CRC by downregulating the fucosylation of MCAM. CONCLUSIONS: The regulation of fucosylation may be an potential therapy for CRC, especially in patients with Fut2 gene defects. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-03906-0. BioMed Central 2023-02-04 /pmc/articles/PMC9899399/ /pubmed/36739428 http://dx.doi.org/10.1186/s12967-023-03906-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Weijun
Tang, Xuelian
Duan, Caihan
Tian, Shuxin
Han, Chaoqun
Qian, Wei
Jiang, Xin
Hou, Xiaohua
Lin, Rong
Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title_full Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title_fullStr Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title_full_unstemmed Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title_short Intestinal epithelium-specific Fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of MCAM
title_sort intestinal epithelium-specific fut2 deficiency promotes colorectal cancer through down-regulating fucosylation of mcam
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899399/
https://www.ncbi.nlm.nih.gov/pubmed/36739428
http://dx.doi.org/10.1186/s12967-023-03906-0
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