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The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer

PURPOSE: Colorectal cancer (CRC) is one of the common causes of cancer death worldwide. Obstructive sleep apnea syndrome (OSAS), sharing many risk factors in common with CRC, is prevalent among CRC patients. OSAS may promote the CRC development independently but the mechanism is still unknown. Inter...

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Autores principales: Gao, Jia, Cao, Hailong, Zhang, Qiang, Wang, Bangmao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195781/
https://www.ncbi.nlm.nih.gov/pubmed/33029691
http://dx.doi.org/10.1007/s11325-020-02204-z
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author Gao, Jia
Cao, Hailong
Zhang, Qiang
Wang, Bangmao
author_facet Gao, Jia
Cao, Hailong
Zhang, Qiang
Wang, Bangmao
author_sort Gao, Jia
collection PubMed
description PURPOSE: Colorectal cancer (CRC) is one of the common causes of cancer death worldwide. Obstructive sleep apnea syndrome (OSAS), sharing many risk factors in common with CRC, is prevalent among CRC patients. OSAS may promote the CRC development independently but the mechanism is still unknown. Intermittent hypoxia (IH) is one of the characteristics of OSAS, and hypoxia may influence the genes associated with CRC. Intestinal microbiota plays important role in CRC carcinogenesis, and OSAS patients have been shown to have intestinal microbiota dysbiosis. We hypothesized that IH and intestinal microbiota dysbiosis may be involved for CRC in patients with OSAS. METHODS: We established precancerous cell models of CRC with Immorto-Min colonic epithelial (IMCE) cells. First, the cells were exposed to IH in a special chamber for 4 h, 8 h, and 12 h. Feces from 6 patients with OSAS and 6 healthy controls were collected and made into sterile fecal fluid for incubation with IMCE cells for 12 h. The cells were then exposed to IH for 4 h, 8 h, and 12 h. After IH exposure, the expressions of genes and inflammation cytokines associated with CRC, such as β-catenin, STAT3, HIF-1α, IL-6, TNF-α, c-myc, and cyclinD1, were tested. RESULTS: IH activated the expression of HIF-1α and STAT3 both in mRNA and protein level (HIF-1α: P = 0.015 for mRNA level, P = 0.027 for protein level; STAT3: P = 0.023 for mRNA level, P = 0.023 for protein level), and promoted p-STAT3 shifting to the nucleus (P = 0.023). The mRNA of β-catenin (P = 0.022) and cyclinD1 (P = 0.023) was elevated, but there was no change for the β-catenin protein in the nucleus. Gut microbiota of OSAS patients promoted the expression of STAT3 (protein level: 0 h: P = 0.037; 4 h: P = 0.046; 8 h: P = 0.049; 12 h: P = 0.037), promoted p-STAT3 (4 h: P = 0.049; 8 h: P = 0.046; 12 h: P = 0.046) shifting to the nucleus, and also elevated the expression of IL-6 and TNF-α in mRNA level at 4 h (IL-6: P = 0.037, TNF-α: P = 0.037) and 8 h (IL-6: P = 0.037, TNF-α: P = 0.037). The protein of β-catenin in the nucleus was not affected by IH and gut microbiota from OSAS. CONCLUSIONS: Our study demonstrated that IH and gut microbiota of patients with OSAS activated HIF-1α expression and STAT3 pathway in IMCE cells, with no influence on β-catenin pathway, which suggested that IH, STAT3 pathway, chronic inflammation, and intestinal microbiota dysbiosis may be involved in CRC carcinogenesis correlated with OSAS These findings must be interpreted cautiously and further research is necessary to clarify the causative steps in CRC development.
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spelling pubmed-81957812021-06-28 The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer Gao, Jia Cao, Hailong Zhang, Qiang Wang, Bangmao Sleep Breath Basic Science • Original Article PURPOSE: Colorectal cancer (CRC) is one of the common causes of cancer death worldwide. Obstructive sleep apnea syndrome (OSAS), sharing many risk factors in common with CRC, is prevalent among CRC patients. OSAS may promote the CRC development independently but the mechanism is still unknown. Intermittent hypoxia (IH) is one of the characteristics of OSAS, and hypoxia may influence the genes associated with CRC. Intestinal microbiota plays important role in CRC carcinogenesis, and OSAS patients have been shown to have intestinal microbiota dysbiosis. We hypothesized that IH and intestinal microbiota dysbiosis may be involved for CRC in patients with OSAS. METHODS: We established precancerous cell models of CRC with Immorto-Min colonic epithelial (IMCE) cells. First, the cells were exposed to IH in a special chamber for 4 h, 8 h, and 12 h. Feces from 6 patients with OSAS and 6 healthy controls were collected and made into sterile fecal fluid for incubation with IMCE cells for 12 h. The cells were then exposed to IH for 4 h, 8 h, and 12 h. After IH exposure, the expressions of genes and inflammation cytokines associated with CRC, such as β-catenin, STAT3, HIF-1α, IL-6, TNF-α, c-myc, and cyclinD1, were tested. RESULTS: IH activated the expression of HIF-1α and STAT3 both in mRNA and protein level (HIF-1α: P = 0.015 for mRNA level, P = 0.027 for protein level; STAT3: P = 0.023 for mRNA level, P = 0.023 for protein level), and promoted p-STAT3 shifting to the nucleus (P = 0.023). The mRNA of β-catenin (P = 0.022) and cyclinD1 (P = 0.023) was elevated, but there was no change for the β-catenin protein in the nucleus. Gut microbiota of OSAS patients promoted the expression of STAT3 (protein level: 0 h: P = 0.037; 4 h: P = 0.046; 8 h: P = 0.049; 12 h: P = 0.037), promoted p-STAT3 (4 h: P = 0.049; 8 h: P = 0.046; 12 h: P = 0.046) shifting to the nucleus, and also elevated the expression of IL-6 and TNF-α in mRNA level at 4 h (IL-6: P = 0.037, TNF-α: P = 0.037) and 8 h (IL-6: P = 0.037, TNF-α: P = 0.037). The protein of β-catenin in the nucleus was not affected by IH and gut microbiota from OSAS. CONCLUSIONS: Our study demonstrated that IH and gut microbiota of patients with OSAS activated HIF-1α expression and STAT3 pathway in IMCE cells, with no influence on β-catenin pathway, which suggested that IH, STAT3 pathway, chronic inflammation, and intestinal microbiota dysbiosis may be involved in CRC carcinogenesis correlated with OSAS These findings must be interpreted cautiously and further research is necessary to clarify the causative steps in CRC development. Springer International Publishing 2020-10-07 2021 /pmc/articles/PMC8195781/ /pubmed/33029691 http://dx.doi.org/10.1007/s11325-020-02204-z Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This 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/) .
spellingShingle Basic Science • Original Article
Gao, Jia
Cao, Hailong
Zhang, Qiang
Wang, Bangmao
The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title_full The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title_fullStr The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title_full_unstemmed The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title_short The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer
title_sort effect of intermittent hypoxia and fecal microbiota of osas on genes associated with colorectal cancer
topic Basic Science • Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195781/
https://www.ncbi.nlm.nih.gov/pubmed/33029691
http://dx.doi.org/10.1007/s11325-020-02204-z
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