MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis

BACKGROUND & AIMS: MUC1 is abnormally expressed in colorectal cancer, including colitis-associated colorectal cancer (CAC), but its role in tumorigenesis is unclear. This study investigated MUC1’s effects in murine models of colitis and CAC and elucidated mechanisms of action. METHODS: Colitis a...

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Autores principales: Sheng, Yong H., Davies, Julie M., Wang, Ran, Wong, Kuan Yau, Giri, Rabina, Yang, Yuanhao, Begun, Jakob, Florin, Timothy H., Hasnain, Sumaira Z., McGuckin, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424590/
https://www.ncbi.nlm.nih.gov/pubmed/35809803
http://dx.doi.org/10.1016/j.jcmgh.2022.06.010
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author Sheng, Yong H.
Davies, Julie M.
Wang, Ran
Wong, Kuan Yau
Giri, Rabina
Yang, Yuanhao
Begun, Jakob
Florin, Timothy H.
Hasnain, Sumaira Z.
McGuckin, Michael A.
author_facet Sheng, Yong H.
Davies, Julie M.
Wang, Ran
Wong, Kuan Yau
Giri, Rabina
Yang, Yuanhao
Begun, Jakob
Florin, Timothy H.
Hasnain, Sumaira Z.
McGuckin, Michael A.
author_sort Sheng, Yong H.
collection PubMed
description BACKGROUND & AIMS: MUC1 is abnormally expressed in colorectal cancer, including colitis-associated colorectal cancer (CAC), but its role in tumorigenesis is unclear. This study investigated MUC1’s effects in murine models of colitis and CAC and elucidated mechanisms of action. METHODS: Colitis and CAC were induced in mice by exposure to dextran sodium sulfate or azoxymethane plus dextran sodium sulphate. Clinical parameters, immune cell infiltration, and tumor development were monitored throughout disease progression. Experiments in knockout mice and bone marrow chimeras were combined with an exploration of immune cell abundance and function. RESULTS: Deficiency of Muc1 suppressed inflammation, inhibited tumor progression, increased abundance of CD8(+) T lymphocytes, and reduced abundance of macrophages in colon tumors. Bone marrow chimeras showed promotion of CAC was primarily mediated by Muc1-expressing hematopoietic cells, and that MUC1 promoted a pro-tumoral immunosuppressive macrophage phenotype within tumors. Mechanistic studies revealed that Muc1 deficiency remarkably reduced interleukin-6 levels in the colonic tissues and tumors that was mainly produced by infiltrating macrophages at day 21, 42, and 85. In bone marrow-derived macrophages, MUC1 promoted responsiveness to chemoattractant and promoted activation into a phenotype with high Il6 and Ido1 expression, secreting factors which inhibited CD8(+) T cell proliferation. MUC1 potently drives macrophages to produce interleukin-6, which in turn drives a pro-tumorigenic activation of signal transducer and activator of transcription 3 in colon epithelial tumor and stromal cells, ultimately increasing the occurrence and development of CAC. CONCLUSIONS: Our findings provide cellular and molecular mechanisms for the pro-tumorigenic functions of MUC1 in the inflamed colon. Therapeutic strategies to inhibit MUC1 signal transduction warrant consideration for the prevention or therapy of CAC.
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spelling pubmed-94245902022-08-31 MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis Sheng, Yong H. Davies, Julie M. Wang, Ran Wong, Kuan Yau Giri, Rabina Yang, Yuanhao Begun, Jakob Florin, Timothy H. Hasnain, Sumaira Z. McGuckin, Michael A. Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: MUC1 is abnormally expressed in colorectal cancer, including colitis-associated colorectal cancer (CAC), but its role in tumorigenesis is unclear. This study investigated MUC1’s effects in murine models of colitis and CAC and elucidated mechanisms of action. METHODS: Colitis and CAC were induced in mice by exposure to dextran sodium sulfate or azoxymethane plus dextran sodium sulphate. Clinical parameters, immune cell infiltration, and tumor development were monitored throughout disease progression. Experiments in knockout mice and bone marrow chimeras were combined with an exploration of immune cell abundance and function. RESULTS: Deficiency of Muc1 suppressed inflammation, inhibited tumor progression, increased abundance of CD8(+) T lymphocytes, and reduced abundance of macrophages in colon tumors. Bone marrow chimeras showed promotion of CAC was primarily mediated by Muc1-expressing hematopoietic cells, and that MUC1 promoted a pro-tumoral immunosuppressive macrophage phenotype within tumors. Mechanistic studies revealed that Muc1 deficiency remarkably reduced interleukin-6 levels in the colonic tissues and tumors that was mainly produced by infiltrating macrophages at day 21, 42, and 85. In bone marrow-derived macrophages, MUC1 promoted responsiveness to chemoattractant and promoted activation into a phenotype with high Il6 and Ido1 expression, secreting factors which inhibited CD8(+) T cell proliferation. MUC1 potently drives macrophages to produce interleukin-6, which in turn drives a pro-tumorigenic activation of signal transducer and activator of transcription 3 in colon epithelial tumor and stromal cells, ultimately increasing the occurrence and development of CAC. CONCLUSIONS: Our findings provide cellular and molecular mechanisms for the pro-tumorigenic functions of MUC1 in the inflamed colon. Therapeutic strategies to inhibit MUC1 signal transduction warrant consideration for the prevention or therapy of CAC. Elsevier 2022-07-06 /pmc/articles/PMC9424590/ /pubmed/35809803 http://dx.doi.org/10.1016/j.jcmgh.2022.06.010 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Sheng, Yong H.
Davies, Julie M.
Wang, Ran
Wong, Kuan Yau
Giri, Rabina
Yang, Yuanhao
Begun, Jakob
Florin, Timothy H.
Hasnain, Sumaira Z.
McGuckin, Michael A.
MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title_full MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title_fullStr MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title_full_unstemmed MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title_short MUC1-mediated Macrophage Activation Promotes Colitis-associated Colorectal Cancer via Activating the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Axis
title_sort muc1-mediated macrophage activation promotes colitis-associated colorectal cancer via activating the interleukin-6/ signal transducer and activator of transcription 3 axis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424590/
https://www.ncbi.nlm.nih.gov/pubmed/35809803
http://dx.doi.org/10.1016/j.jcmgh.2022.06.010
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