TY - JOUR
T1 - Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner
AU - Xu, Dacai
AU - Wu, Jiawen
AU - Dong, Liang
AU - Luo, Wenwen
AU - Li, Lanying
AU - Tang, Daolin
AU - Liu, Jinbao
N1 - Funding Information:
The study was supported by the National Funds for Developing Local Colleges and Universities (B16056001), the Natural Science Foundation research team of Guangdong Province (2018B030312001), the Science and Technology Program of Guangzhou (201604020001), the Innovative Academic Team of Guangzhou Education System (1201610014), the Research Team of Department of Education of Guangdong Province (2017KCXTD027), the Post-doc initiation fund of Guangzhou (011302009), and the Post-doc science research initiation fund of Guangzhou Women and Children’s Medical Center (3001103).
Publisher Copyright:
Copyright © 2021 Xu, Wu, Dong, Luo, Li, Tang and Liu.
PY - 2021/11/22
Y1 - 2021/11/22
N2 - 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.
AB - 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.
KW - apoptosis
KW - liver cancer
KW - macrophage
KW - serpinc1
KW - ubiquitination
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U2 - 10.3389/fonc.2021.738607
DO - 10.3389/fonc.2021.738607
M3 - Article
C2 - 34881176
AN - SCOPUS:85120713529
SN - 2234-943X
VL - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 738607
ER -