Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner

Serpinc1 is a serine protease inhibitor in the coagulation cascade, but its role in tumor biology remains obscure. Here, we report an unexpected role of serpinc1 in suppression of hepatocellular carcinoma (HCC). In HCC patients, the mRNA and protein expression of serpinc1 is upregulated, which is ne...

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Autores principales:	Dacai Xu, Jiawen Wu, Liang Dong, Wenwen Luo, Lanying Li, Daolin Tang, Jinbao Liu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	serpinc1 apoptosis liver cancer macrophage ubiquitination Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/bbfec24f872f46b79240eb408d75fa2c
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spelling	oai:doaj.org-article:bbfec24f872f46b79240eb408d75fa2c2021-11-22T06:26:04ZSerpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner2234-943X10.3389/fonc.2021.738607https://doaj.org/article/bbfec24f872f46b79240eb408d75fa2c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.738607/fullhttps://doaj.org/toc/2234-943XSerpinc1 is a serine protease inhibitor in the coagulation cascade, but its role in tumor biology remains obscure. Here, we report an unexpected role of serpinc1 in suppression of hepatocellular carcinoma (HCC). In HCC patients, the mRNA and protein expression of serpinc1 is upregulated, which is negatively correlated with tumor grade, and has a better prognosis than patients with low serpinc1. In addition, patients with high expression of serpinc1 generally have a better tumor immune microenvironment, accompanied by changes in multiple immune cells and mediators. In particular, tumor-promoting M2 macrophages are negatively correlated with serpinc1 expression and the prognosis of HCC patients. In vitro experiments further show that overexpression of serpinc1 inhibits the growth of HCC cells (HepG2 and SMMC7721) by inducing apoptosis. Accordingly, cell co-culture experiments reveal the direct role of serpinc1-overexpressed HCC cells in inhibiting the formation of M2 macrophages. Subsequent unbiased quantitative proteomic and ubiquitinome analyses identify that multiple poly-ubiquitination of proteins involved in signal pathways (such as autophagy, apoptosis, lactate metabolism, and VEGF signaling) are regulated by serpinc1. Overall, these findings establish a serpinc1-dependent ubiquitin-proteasome system to control apoptosis and antitumor immunity.Dacai XuDacai XuJiawen WuLiang DongWenwen LuoLanying LiDaolin TangJinbao LiuFrontiers Media S.A.articleserpinc1apoptosisliver cancermacrophageubiquitinationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	serpinc1 apoptosis liver cancer macrophage ubiquitination Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	serpinc1 apoptosis liver cancer macrophage ubiquitination Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dacai Xu Dacai Xu Jiawen Wu Liang Dong Wenwen Luo Lanying Li Daolin Tang Jinbao Liu Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
description	Serpinc1 is a serine protease inhibitor in the coagulation cascade, but its role in tumor biology remains obscure. Here, we report an unexpected role of serpinc1 in suppression of hepatocellular carcinoma (HCC). In HCC patients, the mRNA and protein expression of serpinc1 is upregulated, which is negatively correlated with tumor grade, and has a better prognosis than patients with low serpinc1. In addition, patients with high expression of serpinc1 generally have a better tumor immune microenvironment, accompanied by changes in multiple immune cells and mediators. In particular, tumor-promoting M2 macrophages are negatively correlated with serpinc1 expression and the prognosis of HCC patients. In vitro experiments further show that overexpression of serpinc1 inhibits the growth of HCC cells (HepG2 and SMMC7721) by inducing apoptosis. Accordingly, cell co-culture experiments reveal the direct role of serpinc1-overexpressed HCC cells in inhibiting the formation of M2 macrophages. Subsequent unbiased quantitative proteomic and ubiquitinome analyses identify that multiple poly-ubiquitination of proteins involved in signal pathways (such as autophagy, apoptosis, lactate metabolism, and VEGF signaling) are regulated by serpinc1. Overall, these findings establish a serpinc1-dependent ubiquitin-proteasome system to control apoptosis and antitumor immunity.
format	article
author	Dacai Xu Dacai Xu Jiawen Wu Liang Dong Wenwen Luo Lanying Li Daolin Tang Jinbao Liu
author_facet	Dacai Xu Dacai Xu Jiawen Wu Liang Dong Wenwen Luo Lanying Li Daolin Tang Jinbao Liu
author_sort	Dacai Xu
title	Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
title_short	Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
title_full	Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
title_fullStr	Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
title_full_unstemmed	Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
title_sort	serpinc1 acts as a tumor suppressor in hepatocellular carcinoma through inducing apoptosis and blocking macrophage polarization in an ubiquitin-proteasome manner
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/bbfec24f872f46b79240eb408d75fa2c
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Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner

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