MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade

Abstract Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in...

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Autores principales:	Atsuko Tanimura, Akane Nakazato, Nobuyuki Tanaka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/511c17c2004944a2abab9d4c0af364f7
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spelling	oai:doaj.org-article:511c17c2004944a2abab9d4c0af364f72021-12-02T12:11:28ZMYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade10.1038/s41598-021-83603-42045-2322https://doaj.org/article/511c17c2004944a2abab9d4c0af364f72021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83603-4https://doaj.org/toc/2045-2322Abstract Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in mice and its gene mutation was found in human cancers. In inflammation-induced colon cancer, tumour suppressor p53 mutations have also been detected with high frequency as early events. However, the molecular mechanism of MYD88-induced cancer development is poorly understood. Here, we demonstrated that MYD88 induced the protein accumulation of the transcription factor HIF-1α through NF-κB in p53-deficient cells. HIF-1α accumulation was not caused by enhanced protein stability but by NF-κB-mediated transcriptional activation, the enhanced translation of HIF-1α and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1α and HIF-1-target genes were attenuated in the presence of p53. Furthermore, constitutively active forms of MYD88 induced tumour-initiating cell (TIC) generation in p53-deficient cells, as determined by tumour xenografts in nude mice. TIC generating activity was diminished by the suppression of NF-κB or HIF-1α. These results indicate that MYD88 signals induce the generation of TICs through the NF-κB-HIF-1α activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.Atsuko TanimuraAkane NakazatoNobuyuki TanakaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atsuko Tanimura Akane Nakazato Nobuyuki Tanaka MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
description	Abstract Tumour-promoting inflammation is a hallmark of cancer, and chronic inflammatory disease increases the risk of cancer. In this context, MYD88, a downstream signalling molecule of Toll-like receptors that initiates inflammatory signalling cascades, has a critical role in tumour development in mice and its gene mutation was found in human cancers. In inflammation-induced colon cancer, tumour suppressor p53 mutations have also been detected with high frequency as early events. However, the molecular mechanism of MYD88-induced cancer development is poorly understood. Here, we demonstrated that MYD88 induced the protein accumulation of the transcription factor HIF-1α through NF-κB in p53-deficient cells. HIF-1α accumulation was not caused by enhanced protein stability but by NF-κB-mediated transcriptional activation, the enhanced translation of HIF-1α and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1α and HIF-1-target genes were attenuated in the presence of p53. Furthermore, constitutively active forms of MYD88 induced tumour-initiating cell (TIC) generation in p53-deficient cells, as determined by tumour xenografts in nude mice. TIC generating activity was diminished by the suppression of NF-κB or HIF-1α. These results indicate that MYD88 signals induce the generation of TICs through the NF-κB-HIF-1α activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.
format	article
author	Atsuko Tanimura Akane Nakazato Nobuyuki Tanaka
author_facet	Atsuko Tanimura Akane Nakazato Nobuyuki Tanaka
author_sort	Atsuko Tanimura
title	MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
title_short	MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
title_full	MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
title_fullStr	MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
title_full_unstemmed	MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade
title_sort	myd88 signals induce tumour-initiating cell generation through the nf-κb-hif-1α activation cascade
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/511c17c2004944a2abab9d4c0af364f7
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MYD88 signals induce tumour-initiating cell generation through the NF-κB-HIF-1α activation cascade

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