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KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma
BACKGROUND: Early metastasis is a hallmark of osteosarcoma (OS), a highly common type of malignant tumor. Members of the potassium inwardly rectifying channel family exert oncogenic effects in various cancers. However, the role of the potassium inwardly rectifying channel subfamily J member 2 (KCNJ2...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979522/ https://www.ncbi.nlm.nih.gov/pubmed/36864422 http://dx.doi.org/10.1186/s12964-023-01064-w |
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author | Shen, Mao Pan, Runsang Lei, Shan Zhang, Lu Zhou, Changhua Zeng, Zhirui Nie, Yingjie Tian, Xiaobin |
author_facet | Shen, Mao Pan, Runsang Lei, Shan Zhang, Lu Zhou, Changhua Zeng, Zhirui Nie, Yingjie Tian, Xiaobin |
author_sort | Shen, Mao |
collection | PubMed |
description | BACKGROUND: Early metastasis is a hallmark of osteosarcoma (OS), a highly common type of malignant tumor. Members of the potassium inwardly rectifying channel family exert oncogenic effects in various cancers. However, the role of the potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) in OS is unclear. METHODS: The expression of KCNJ2 in OS tissues and cell lines was measured using bioinformatic analysis, immunohistochemistry, and western blotting. Wound-healing assays, Transwell assays, and lung metastasis models were used to analyze the effects of KCNJ2 on mobility of OS cells. The molecular mechanisms linking KCNJ2 and HIF1α in OS were explored by mass spectrometry analysis, immunoprecipitation, ubiquitination detection, and chromatin-immunoprecipitation quantitative real-time polymerase chain reaction. RESULTS: KCNJ2 was found to be overexpressed in advanced-stage OS tissues, as well as in cells with high metastatic potential. High expression of KCNJ2 was associated with a shorter survival rate of OS patients. KCNJ2-inhibition repressed the metastasis of OS cells, whereas KCNJ2-elevation induced the opposite effects. Mechanistically, KCNJ2 binds to HIF1α and inhibits its ubiquitination, thus increasing the expression of HIF1α. Interestingly, HIF1α binds directly to the KCNJ2 promoter and increases its transcription under hypoxic conditions. CONCLUSION: Taken together, our results indicated that a KCNJ2/HIF1α positive feedback loop exists in OS tissues, which significantly promotes OS cell metastasis. This evidence may contribute to the diagnosis and treatment of OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-023-01064-w. |
format | Online Article Text |
id | pubmed-9979522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-99795222023-03-03 KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma Shen, Mao Pan, Runsang Lei, Shan Zhang, Lu Zhou, Changhua Zeng, Zhirui Nie, Yingjie Tian, Xiaobin Cell Commun Signal Research BACKGROUND: Early metastasis is a hallmark of osteosarcoma (OS), a highly common type of malignant tumor. Members of the potassium inwardly rectifying channel family exert oncogenic effects in various cancers. However, the role of the potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) in OS is unclear. METHODS: The expression of KCNJ2 in OS tissues and cell lines was measured using bioinformatic analysis, immunohistochemistry, and western blotting. Wound-healing assays, Transwell assays, and lung metastasis models were used to analyze the effects of KCNJ2 on mobility of OS cells. The molecular mechanisms linking KCNJ2 and HIF1α in OS were explored by mass spectrometry analysis, immunoprecipitation, ubiquitination detection, and chromatin-immunoprecipitation quantitative real-time polymerase chain reaction. RESULTS: KCNJ2 was found to be overexpressed in advanced-stage OS tissues, as well as in cells with high metastatic potential. High expression of KCNJ2 was associated with a shorter survival rate of OS patients. KCNJ2-inhibition repressed the metastasis of OS cells, whereas KCNJ2-elevation induced the opposite effects. Mechanistically, KCNJ2 binds to HIF1α and inhibits its ubiquitination, thus increasing the expression of HIF1α. Interestingly, HIF1α binds directly to the KCNJ2 promoter and increases its transcription under hypoxic conditions. CONCLUSION: Taken together, our results indicated that a KCNJ2/HIF1α positive feedback loop exists in OS tissues, which significantly promotes OS cell metastasis. This evidence may contribute to the diagnosis and treatment of OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-023-01064-w. BioMed Central 2023-03-02 /pmc/articles/PMC9979522/ /pubmed/36864422 http://dx.doi.org/10.1186/s12964-023-01064-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Shen, Mao Pan, Runsang Lei, Shan Zhang, Lu Zhou, Changhua Zeng, Zhirui Nie, Yingjie Tian, Xiaobin KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title | KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title_full | KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title_fullStr | KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title_full_unstemmed | KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title_short | KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma |
title_sort | kcnj2/hif1α positive-feedback loop promotes the metastasis of osteosarcoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979522/ https://www.ncbi.nlm.nih.gov/pubmed/36864422 http://dx.doi.org/10.1186/s12964-023-01064-w |
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