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Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway

BACKGROUND: Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial. METHODS: The para...

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Autores principales: Wu, Zhengzhong, Yan, Leye, Lin, Junqing, Ke, Kun, Yang, Weizhu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522106/
https://www.ncbi.nlm.nih.gov/pubmed/34657635
http://dx.doi.org/10.1186/s12935-021-02228-9
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author Wu, Zhengzhong
Yan, Leye
Lin, Junqing
Ke, Kun
Yang, Weizhu
author_facet Wu, Zhengzhong
Yan, Leye
Lin, Junqing
Ke, Kun
Yang, Weizhu
author_sort Wu, Zhengzhong
collection PubMed
description BACKGROUND: Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial. METHODS: The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer. RESULTS: Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice. CONCLUSIONS: Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.
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spelling pubmed-85221062021-10-21 Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway Wu, Zhengzhong Yan, Leye Lin, Junqing Ke, Kun Yang, Weizhu Cancer Cell Int Primary Research BACKGROUND: Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial. METHODS: The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer. RESULTS: Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice. CONCLUSIONS: Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy. BioMed Central 2021-10-17 /pmc/articles/PMC8522106/ /pubmed/34657635 http://dx.doi.org/10.1186/s12935-021-02228-9 Text en © The Author(s) 2021 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 Primary Research
Wu, Zhengzhong
Yan, Leye
Lin, Junqing
Ke, Kun
Yang, Weizhu
Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title_full Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title_fullStr Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title_full_unstemmed Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title_short Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway
title_sort constitutive tdo2 expression promotes liver cancer progression by an autocrine il-6 signaling pathway
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522106/
https://www.ncbi.nlm.nih.gov/pubmed/34657635
http://dx.doi.org/10.1186/s12935-021-02228-9
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