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Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway
As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hyp...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160999/ https://www.ncbi.nlm.nih.gov/pubmed/37094129 http://dx.doi.org/10.1073/pnas.2218033120 |
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author | Akimoto, Miho Susa, Takao Okudaira, Noriyuki Koshikawa, Nobuko Hisaki, Harumi Iizuka, Masayoshi Okinaga, Hiroko Takenaga, Keizo Okazaki, Tomoki Tamamori-Adachi, Mimi |
author_facet | Akimoto, Miho Susa, Takao Okudaira, Noriyuki Koshikawa, Nobuko Hisaki, Harumi Iizuka, Masayoshi Okinaga, Hiroko Takenaga, Keizo Okazaki, Tomoki Tamamori-Adachi, Mimi |
author_sort | Akimoto, Miho |
collection | PubMed |
description | As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC. |
format | Online Article Text |
id | pubmed-10160999 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-101609992023-10-24 Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway Akimoto, Miho Susa, Takao Okudaira, Noriyuki Koshikawa, Nobuko Hisaki, Harumi Iizuka, Masayoshi Okinaga, Hiroko Takenaga, Keizo Okazaki, Tomoki Tamamori-Adachi, Mimi Proc Natl Acad Sci U S A Biological Sciences As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC. National Academy of Sciences 2023-04-24 2023-05-02 /pmc/articles/PMC10160999/ /pubmed/37094129 http://dx.doi.org/10.1073/pnas.2218033120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Akimoto, Miho Susa, Takao Okudaira, Noriyuki Koshikawa, Nobuko Hisaki, Harumi Iizuka, Masayoshi Okinaga, Hiroko Takenaga, Keizo Okazaki, Tomoki Tamamori-Adachi, Mimi Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title | Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title_full | Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title_fullStr | Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title_full_unstemmed | Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title_short | Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF–nuclear IL-33–GATA3 pathway |
title_sort | hypoxia induces downregulation of the tumor-suppressive sst2 in colorectal cancer cells via the hif–nuclear il-33–gata3 pathway |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160999/ https://www.ncbi.nlm.nih.gov/pubmed/37094129 http://dx.doi.org/10.1073/pnas.2218033120 |
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