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.
ObjectiveCancer-associated mesenchymal stem cells (MSCs) regulate the progression of cancers through exosome-delivered components, while few studies are conducted on hepatocellular carcinoma (HCC). This study aimed to evaluate the effect of exosomes from HCC-associated MSCs (HCC-MSCs) on HCC cellular functions and the potential regulatory mechanism.MethodsHCC cells (Huh7 and PLC) were cultured normally or co-cultured with HCC-MSCs, HCC-MSCs plus GW4869, or HCC-MSC-derived exosomes; then mRNA sequencing and RT-qPCR validation were conducted. Subsequently, candidate genes were sorted out and modified in HCC cells. Next, TMBIM6-modified HCC-MSCs were used to treat HCC cells.ResultsBoth HCC-MSCs and their derived exosomes promoted proliferation, invasion, sphere formation ability but suppressed apoptosis in HCC cells (all p < 0.05); however, the effect of HCC-MSCs on these cellular functions was repressed by exosome inhibitor (GW4869). Subsequently, TMBIM6, EEF2, and PRDX1 were sorted out by mRNA sequencing and RT-qPCR validation as candidate genes implicated in the regulation of HCC cellular functions by HCC-MSC-derived exosomes. Among them, TMBIM6 had a potent effect (all p < 0.05), while EEF2 and PRDX1 had less effect on regulating HCC cell viability and invasion. Next, direct silencing TMBIM6 repressed viability, sphere formation, invasion, epithelial–mesenchymal transition (EMT), and PI3K/AKT pathway but promoted apoptosis in HCC cells; however, overexpressing TMBIM6 showed the opposite effect. Furthermore, incubating with exosomes from TMBIM6-modified HCC-MSCs presented a similar effect as direct TMBIM6 modification in HCC cells.ConclusionHCC-MSC-derived exosomes transmit TMBIM6 to promote malignant behavior via PI3K/AKT pathway in HCC.
Background: Great advance has been achieved in the investigation of Hippo signaling on mediating carcinogenesis. However, the underlying mechanism that YAP1/TEAD4 signaling regulated hepatocellular carcinoma (HCC) progression have not been completely determined. This investigation aimed to determine the mechanism of activation of YAP1/TEAD4 pathway and its regulatory effect on hepatocarcinogenesis.Methods: The TCGA database and immunohistochemical (IHC) analyses about HCC samples were carried out to analyze the expression of TEAD4 and its correlation with HCC prognosis. CCK-8, wound healing assay and transwell chamber with Matrigel were used to examine the role of TEAD4 on cell proliferation, migration and invasion capacities. In vivo imaging system was used to observe the tumor formation in SCID mouse model. The mechanistic investigation was conducted with functional studies, Western immunoblotting, Luciferase reporter assay, chromatin immunoprecipitation.Results: Analysis of HCC samples revealed that TEAD4 was up-regulated in HCC tissues compared to adjacent liver tissues, and its overexpression in HCC was significantly associated with worse prognosis, high serum AFP level, larger tumor size, PVTT, multiple tumor lesions, and microvascular invasion. Enforced expression of TEAD4 in HCC cell lines promoted the proliferation and growth of HCC cells in vitro and in vivo. The further functional studies showed that TEAD4 increased TWIST1 expression directly in the binding-promoter manner and then enhanced the migration and invasion of HCC cells via inducing epithelial-to-mesenchymal transition (EMT).TWIST1 was found to enhance E2R expression and consequently formed a positive feedback loop to activate the YAP1/TEAD4/TWIST1 axis.Conclusion: This investigation provided the functional and mechanistic basis for identifying the E2R/YAP1/TEAD4/TWIST axis as the oncogenic factor which inducing EMT and then accelerated HCC growth and invasion.
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