Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma

Accumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA)...

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Autores principales:	Yihang Gong, Kun Li, Yunfei Qin, Kaining Zeng, Jianrong Liu, Shaozhuo Huang, Yewu Chen, Haoyuan Yu, Wei Liu, Linsen Ye, Yang Yang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	hepatocellular carcinoma (HCC) bile acids exosomes immune microenvironment Farnesoid X receptor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4edb1c5afafa4b80a3d6fcaefbea4214
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spelling	oai:doaj.org-article:4edb1c5afafa4b80a3d6fcaefbea42142021-11-30T11:23:09ZNorcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma2234-943X10.3389/fonc.2021.711448https://doaj.org/article/4edb1c5afafa4b80a3d6fcaefbea42142021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.711448/fullhttps://doaj.org/toc/2234-943XAccumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA) in HCC progression remain unknown yet. In this study, herein we demonstrate that NorCA can promote HCC cell proliferation, migration and invasion through negatively regulating FXR. Additionally, NorCA can increase PD-L1 level on the surfaces of HCC cells and their exosomes, and NorCA-induced exosomes dramatically dampen the function of CD4+T cells, thereby inducing an immunosuppressive microenvironment. Meanwhile, a negative correlation between PD-L1 and FXR expression in human HCC specimens was identified, and HCC patients with FXRlowPD-L1high expression exhibit a rather dismal survival outcome. Importantly, FXR agonist (GW4064) can synergize with anti-PD-1 antibody (Ab) to inhibit HCC growth in tumor-bearing models. Taken together, NorCA can promote HCC progression and immune invasion by inhibiting FXR signaling, implying a superiority of the combination of FXR agonist and anti‐PD‐1 Ab to the monotherapy of immune checkpoint inhibitor in combating HCC. However, more well-designed animal experiments and clinical trials are warranted to further confirm our findings in future due to the limitations in our study.Yihang GongYihang GongKun LiKun LiYunfei QinKaining ZengJianrong LiuShaozhuo HuangYewu ChenYewu ChenHaoyuan YuHaoyuan YuWei LiuWei LiuLinsen YeLinsen YeYang YangFrontiers Media S.A.articlehepatocellular carcinoma (HCC)bile acidsexosomesimmune microenvironmentFarnesoid X receptorNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hepatocellular carcinoma (HCC) bile acids exosomes immune microenvironment Farnesoid X receptor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	hepatocellular carcinoma (HCC) bile acids exosomes immune microenvironment Farnesoid X receptor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yihang Gong Yihang Gong Kun Li Kun Li Yunfei Qin Kaining Zeng Jianrong Liu Shaozhuo Huang Yewu Chen Yewu Chen Haoyuan Yu Haoyuan Yu Wei Liu Wei Liu Linsen Ye Linsen Ye Yang Yang Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
description	Accumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA) in HCC progression remain unknown yet. In this study, herein we demonstrate that NorCA can promote HCC cell proliferation, migration and invasion through negatively regulating FXR. Additionally, NorCA can increase PD-L1 level on the surfaces of HCC cells and their exosomes, and NorCA-induced exosomes dramatically dampen the function of CD4+T cells, thereby inducing an immunosuppressive microenvironment. Meanwhile, a negative correlation between PD-L1 and FXR expression in human HCC specimens was identified, and HCC patients with FXRlowPD-L1high expression exhibit a rather dismal survival outcome. Importantly, FXR agonist (GW4064) can synergize with anti-PD-1 antibody (Ab) to inhibit HCC growth in tumor-bearing models. Taken together, NorCA can promote HCC progression and immune invasion by inhibiting FXR signaling, implying a superiority of the combination of FXR agonist and anti‐PD‐1 Ab to the monotherapy of immune checkpoint inhibitor in combating HCC. However, more well-designed animal experiments and clinical trials are warranted to further confirm our findings in future due to the limitations in our study.
format	article
author	Yihang Gong Yihang Gong Kun Li Kun Li Yunfei Qin Kaining Zeng Jianrong Liu Shaozhuo Huang Yewu Chen Yewu Chen Haoyuan Yu Haoyuan Yu Wei Liu Wei Liu Linsen Ye Linsen Ye Yang Yang
author_facet	Yihang Gong Yihang Gong Kun Li Kun Li Yunfei Qin Kaining Zeng Jianrong Liu Shaozhuo Huang Yewu Chen Yewu Chen Haoyuan Yu Haoyuan Yu Wei Liu Wei Liu Linsen Ye Linsen Ye Yang Yang
author_sort	Yihang Gong
title	Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
title_short	Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
title_full	Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
title_fullStr	Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
title_full_unstemmed	Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma
title_sort	norcholic acid promotes tumor progression and immune escape by regulating farnesoid x receptor in hepatocellular carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/4edb1c5afafa4b80a3d6fcaefbea4214
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Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma

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