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Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H(2)S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune e...

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Autores principales: Zhou, Yu-Fu, Song, Shu-Shu, Tian, Meng-Xin, Tang, Zheng, Wang, Han, Fang, Yuan, Qu, Wei-Feng, Jiang, Xi-Fei, Tao, Chen-Yang, Huang, Run, Zhou, Pei-Yun, Zhu, Shi-Guo, Zhou, Jian, Fan, Jia, Liu, Wei-Ren, Shi, Ying-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380548/
https://www.ncbi.nlm.nih.gov/pubmed/34413167
http://dx.doi.org/10.1136/jitc-2021-003031
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author Zhou, Yu-Fu
Song, Shu-Shu
Tian, Meng-Xin
Tang, Zheng
Wang, Han
Fang, Yuan
Qu, Wei-Feng
Jiang, Xi-Fei
Tao, Chen-Yang
Huang, Run
Zhou, Pei-Yun
Zhu, Shi-Guo
Zhou, Jian
Fan, Jia
Liu, Wei-Ren
Shi, Ying-Hong
author_facet Zhou, Yu-Fu
Song, Shu-Shu
Tian, Meng-Xin
Tang, Zheng
Wang, Han
Fang, Yuan
Qu, Wei-Feng
Jiang, Xi-Fei
Tao, Chen-Yang
Huang, Run
Zhou, Pei-Yun
Zhu, Shi-Guo
Zhou, Jian
Fan, Jia
Liu, Wei-Ren
Shi, Ying-Hong
author_sort Zhou, Yu-Fu
collection PubMed
description BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H(2)S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC. METHODS: 236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS. RESULTS: Downregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H(2)S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC. CONCLUSIONS: Our results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy.
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spelling pubmed-83805482021-09-08 Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis Zhou, Yu-Fu Song, Shu-Shu Tian, Meng-Xin Tang, Zheng Wang, Han Fang, Yuan Qu, Wei-Feng Jiang, Xi-Fei Tao, Chen-Yang Huang, Run Zhou, Pei-Yun Zhu, Shi-Guo Zhou, Jian Fan, Jia Liu, Wei-Ren Shi, Ying-Hong J Immunother Cancer Basic Tumor Immunology BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H(2)S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC. METHODS: 236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS. RESULTS: Downregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H(2)S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC. CONCLUSIONS: Our results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy. BMJ Publishing Group 2021-08-19 /pmc/articles/PMC8380548/ /pubmed/34413167 http://dx.doi.org/10.1136/jitc-2021-003031 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Zhou, Yu-Fu
Song, Shu-Shu
Tian, Meng-Xin
Tang, Zheng
Wang, Han
Fang, Yuan
Qu, Wei-Feng
Jiang, Xi-Fei
Tao, Chen-Yang
Huang, Run
Zhou, Pei-Yun
Zhu, Shi-Guo
Zhou, Jian
Fan, Jia
Liu, Wei-Ren
Shi, Ying-Hong
Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title_full Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title_fullStr Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title_full_unstemmed Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title_short Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis
title_sort cystathionine β-synthase mediated prrx2/il-6/stat3 inactivation suppresses tregs infiltration and induces apoptosis to inhibit hcc carcinogenesis
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380548/
https://www.ncbi.nlm.nih.gov/pubmed/34413167
http://dx.doi.org/10.1136/jitc-2021-003031
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