Cargando…

Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

BACKGROUND: Sulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Cong, Shang, Chuzhi, Gai, Xiaohong, Song, Tao, Han, Shaoshan, Liu, Qingguang, Zheng, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056031/
https://www.ncbi.nlm.nih.gov/pubmed/33889573
http://dx.doi.org/10.3389/fcell.2021.631931
_version_ 1783680567538089984
author Wang, Cong
Shang, Chuzhi
Gai, Xiaohong
Song, Tao
Han, Shaoshan
Liu, Qingguang
Zheng, Xin
author_facet Wang, Cong
Shang, Chuzhi
Gai, Xiaohong
Song, Tao
Han, Shaoshan
Liu, Qingguang
Zheng, Xin
author_sort Wang, Cong
collection PubMed
description BACKGROUND: Sulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated fibroblasts (CAFs) in the hepatocellular carcinoma (HCC) microenvironment and the mechanism underlying CAF-mediated HCC growth. METHODS: The clinical relevance of SULF2 and CAFs was examined using in silico and immunohistochemical (IHC) analyses. Functional studies were performed to evaluate the role of SULF2 in the differentiation of HSCs into CAFs and elucidate the mechanism underlying CAF-mediated HCC growth. Mechanistic studies were performed using the chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays. The in vitro findings were verified using the nude HCC xenograft mouse model. RESULTS: The Cancer Genome Atlas (TCGA) database and IHC analyses revealed that the expression of CAF markers, which was positively correlated with that of SULF2 in the HCC tissues, predicted unfavorable postsurgical outcomes. Co-culturing HSCs with HCC cells expressing SULF2 promoted CAF differentiation. Additionally, CAFs repressed HCC cell apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway. Meanwhile, SULF2-induced CAFs promoted epithelial-to-mesenchymal transition (EMT) of HCC cells by modulating the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. Studies using HCC xenograft mouse models demonstrated that OIP5-AS1 induced EMT by upregulating SNAI1 and promoted HCC growth in vivo. CONCLUSION: These data indicated that SULF2 secreted by the HCC cells induced the differentiation of HSCs into CAFs through the TGFβ1/SMAD3 signaling pathway. SULF2-induced CAFs attenuated HCC apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway and induced EMT through the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. This study revealed a novel mechanism involved in the crosstalk between HCC cells and CAFs in the tumor microenvironment, which can aid in the development of novel and efficient therapeutic strategies for primary liver cancer.
format Online
Article
Text
id pubmed-8056031
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-80560312021-04-21 Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition Wang, Cong Shang, Chuzhi Gai, Xiaohong Song, Tao Han, Shaoshan Liu, Qingguang Zheng, Xin Front Cell Dev Biol Cell and Developmental Biology BACKGROUND: Sulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated fibroblasts (CAFs) in the hepatocellular carcinoma (HCC) microenvironment and the mechanism underlying CAF-mediated HCC growth. METHODS: The clinical relevance of SULF2 and CAFs was examined using in silico and immunohistochemical (IHC) analyses. Functional studies were performed to evaluate the role of SULF2 in the differentiation of HSCs into CAFs and elucidate the mechanism underlying CAF-mediated HCC growth. Mechanistic studies were performed using the chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays. The in vitro findings were verified using the nude HCC xenograft mouse model. RESULTS: The Cancer Genome Atlas (TCGA) database and IHC analyses revealed that the expression of CAF markers, which was positively correlated with that of SULF2 in the HCC tissues, predicted unfavorable postsurgical outcomes. Co-culturing HSCs with HCC cells expressing SULF2 promoted CAF differentiation. Additionally, CAFs repressed HCC cell apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway. Meanwhile, SULF2-induced CAFs promoted epithelial-to-mesenchymal transition (EMT) of HCC cells by modulating the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. Studies using HCC xenograft mouse models demonstrated that OIP5-AS1 induced EMT by upregulating SNAI1 and promoted HCC growth in vivo. CONCLUSION: These data indicated that SULF2 secreted by the HCC cells induced the differentiation of HSCs into CAFs through the TGFβ1/SMAD3 signaling pathway. SULF2-induced CAFs attenuated HCC apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway and induced EMT through the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. This study revealed a novel mechanism involved in the crosstalk between HCC cells and CAFs in the tumor microenvironment, which can aid in the development of novel and efficient therapeutic strategies for primary liver cancer. Frontiers Media S.A. 2021-04-06 /pmc/articles/PMC8056031/ /pubmed/33889573 http://dx.doi.org/10.3389/fcell.2021.631931 Text en Copyright © 2021 Wang, Shang, Gai, Song, Han, Liu and Zheng. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Wang, Cong
Shang, Chuzhi
Gai, Xiaohong
Song, Tao
Han, Shaoshan
Liu, Qingguang
Zheng, Xin
Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title_full Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title_fullStr Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title_full_unstemmed Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title_short Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition
title_sort sulfatase 2-induced cancer-associated fibroblasts promote hepatocellular carcinoma progression via inhibition of apoptosis and induction of epithelial-to-mesenchymal transition
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056031/
https://www.ncbi.nlm.nih.gov/pubmed/33889573
http://dx.doi.org/10.3389/fcell.2021.631931
work_keys_str_mv AT wangcong sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT shangchuzhi sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT gaixiaohong sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT songtao sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT hanshaoshan sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT liuqingguang sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition
AT zhengxin sulfatase2inducedcancerassociatedfibroblastspromotehepatocellularcarcinomaprogressionviainhibitionofapoptosisandinductionofepithelialtomesenchymaltransition