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MYD88 signals induce tumour-initiating cell generation through the NF-?B-HIF-1? 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 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-1? through NF-?B in p53-deficient cells. HIF-1? accumulation was not caused by enhanced protein stability but by NF-?B-mediated transcriptional activation, the enhanced translation of HIF-1? and JNK activation. In contrast, MYD88-induced mRNA expressions of HIF-1? 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-?B or HIF-1?. These results indicate that MYD88 signals induce the generation of TICs through the NF-?B-HIF-1? activation cascade in p53-deficient cells and suggest this molecular mechanism underlies inflammation-induced cancer development.

SUBMITTER: Tanimura A

PROVIDER: S-EPMC7890054 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Tanimura Atsuko A Nakazato Akane A Tanaka Nobuyuki N

Scientific reports 20210217 1

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 ...[more]

PMID: 33597599

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Dataset Information

MYD88 signals induce tumour-initiating cell generation through the NF-?B-HIF-1? activation cascade.

Publications

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

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