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

Abstract

BackgroundSulfatase 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.MethodsThe 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.ResultsThe 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.ConclusionThese 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.

Aberrant accumulation of NIK promotes tumorigenicity by dysregulating post-translational modifications in breast cancer

“…It is possible that a reduction in the number of CAFs in tumors by NIK knockdown contributes to the decline in the antiapoptotic potency of cancer cells. CXCL12/SDF-1 secreted by CAFs contributes to tumor growth and anti-apoptosis in cancer cells via CXCR4 39,40 . Indeed, the expression of CXCR4 was reduced in NIK knockdown cells; thus, there was a deficiency in the positive feedback through this paracrine mechanism.…”

SULF2 Is a Prognostic Biomarker and Correlated with Tumor Associated Macrophages in Gastric Cancer

“…So chrysin antiproliferative action against GC cells might also be attributed to the suppression of SULF2. Inhibitors of SULFs are under study 12 , and, once these have been developed to the stage where they are suitable for cell-based and preferably in vivo studies, the therapeutic potential of SULF2 inhibition can be explored. It is possible that such compounds could counteract the effect of SULF2 by sequestering growth factors released in the extracellular and pericellular space 18 .…”

The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment

“…The activation of the TGF-β/SMAD pathway induces type I and III collagen expression in human HSC line LX2. It has been confirmed that SULF2 expressed by HCC cells can induce HSCs into CAFs through the TGF-β/SMAD3 pathway, which may further inhibit apoptosis and promote EMT of HCC cells via the SDF-1/CXCR4-related signaling pathway ( 20 ). p300 acetyltransferase promotes TGF-β-stimulated HSC activation by both cytoplasm-to-nucleus shuttle for SMAD2/3-tafazzin (TAZ) and histone acetylation mechanisms ( 26 ).…”

“…Quiescent hepatic stellate cells (HSCs) and other normal fibroblasts suppress malignant cell growth via contact inhibition (18). While under liver injury, the inflammatory factors including sulfatase (SULF)-2, transforming growth factor (TGF)-b, CXCL6, and CXCR4 educate normal fibroblasts and other relevant cells toward CAFs (20)(21)(22) and increase the expression of CAF markers such as a-smooth muscle actin (SMA), FAP, vimentin, collagen, and fibroblast specific protein (FSP)-1 (23). The mechanisms for CAF activation are summarized in Figure 1.…”