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: | , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/511c17c2004944a2abab9d4c0af364f7 |
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| Sumario: | 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. |
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