Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DSE regulates the malignant characters of hepatocellular carcinoma cells by modulating CCL5/CCR1 axis.

ABSTRACT: Abnormal expression of dermatan sulfate epimerase (DSE) has been found in many types of cancer, while its expression and biological functions in hepatocellular carcinoma (HCC) progression remains obscure. Here we report that DSE, the enzyme that catalyzes the conversion of chondroitin sulfate (CS) to dermatan sulfate (DS), is a critical mediator of malignant character in HCC, through regulation of CCL5 signaling. DSE mRNA and protein were downregulated frequently in HCC tumors, where these events were associated with advanced tumor stages, metastases, and poor survival. DSE-mediated tumor growth was evaluated in immune-deficient and immune-complement mice models. Restoring DSE expression in HCC cells suppressed tumor growth, as well as decreased IL-1β and CCL5 levels in transplanted tumor tissue. Mechanistic investigations revealed that the expression of DSE altered CCL5 signaling and cell surface binding in HCC cells. Accordingly, DSE suppressed CCL5-induced cell growth, migration, and invasion, whereas silencing of DSE enhanced CCL5-triggered malignant phenotypes. Inhibiting CCR1 activity with BX471 decreased CCL5-induced malignant characters caused by siRNA-mediated knockdown of DSE in HCC cells, establishing the critical role of the CCL5/CCR1 axis in mediating the effects of DSE expression. Taken together, our results suggest that DSE dysregulation contributes to the malignant behavior of HCC cells. This provides novel insight into the significance of DSE in CCL5 signaling and HCC pathogenesis.

SUBMITTER: Liao WC

PROVIDER: S-EPMC6405965 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma.

Project description:Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.

| S-EPMC7226629 | biostudies-literature

Epigenetic Modification of the CCL5/CCR1/ERK Axis Enhances Glioma Targeting in Dedifferentiation-Reprogrammed BMSCs.

Project description:The success of stem cell-mediated gene therapy in cancer treatment largely depends on the specific homing ability of stem cells. We have previously demonstrated that after in vitro induction of neuronal differentiation and dedifferentiation, bone marrow stromal cells (BMSCs) revert to a primitive stem cell population (De-neu-BMSCs) distinct from naive BMSCs. We report here that De-neu-BMSCs express significantly higher levels of chemokines, and display enhanced homing abilities to glioma, the effect of which is mediated by the activated CCL5/CCR1/ERK axis. Intriguingly, we find that the activated chemokine axis in De-neu-BMSCs is epigenetically regulated by histone modifications. On the therapeutic front, we show that De-neu-BMSCs elicit stronger homing and glioma-killing effects together with cytosine deaminase/5-fluorocytosine compared with unmanipulated BMSCs in vivo. Altogether, the current study provides an insight into chemokine regulation in BMSCs, which may have more profound effects on BMSC function and their application in regenerative medicine and cancer targeting.

| S-EPMC5355636 | biostudies-literature

Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis.

Project description:Cancer-associated fibroblasts (CAFs) are one of the most enriched components of Hepatocellular carcinoma (HCC) microenvironment, which are tightly related to the metastasis and invasion of HCC. We identified a mechanism by which CAF-derived chemokine CCL5 enhanced HCC metastasis by triggering the HIF1α/ZEB1 axis. We demonstrated that CAFs derived from HCC tissues promoted the migration and invasion of HCC cells and facilitated metastasis to the lung of NOD/SCID mice. Then the chemokine antibody array elucidated the higher chemokine CCL5 level secreted by CAFs than by paracancerous tissue fibroblasts (PTFs). Mechanistically, we found that CAF-derived CCL5 inhibited the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) by binding to specific receptors, maintained HIF1α under normoxia, thereby up-regulated the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and induced epithelial-mesenchymal transition (EMT), ultimately validating its ability to promote lung metastasis of HCC. And this novel mechanism may have association with poor prognosis. Taken together, targeting CAF-derived CCL5 mediated HIF1α/ZEB1 cascade possibly propose a new therapeutic route for HCC.

| S-EPMC9119971 | biostudies-literature

EZH2 promotes hepatocellular carcinoma progression through modulating miR-22/galectin-9 axis.

Project description:BACKGROUND:Recent studies have shown that interferon-γ (IFN-γ)-induced galectin-9 expression in Kupffer cells plays an essential role in modulatingthe microenvironment of hepatitis-associated hepatocellular carcinoma (HCC). However, whether or not IFN-γ induces galectin-9 expression in HCC cells, its biological role and regulatory mechanism in HCC development and progression are poorly defined. METHODS:Quantitative PCR and western blotting analysis were used to detect galectin-9 and EZH2 levels in HCC cell lines stimulated with IFN-γ. Bioinformatics analysis and luciferase reporter assay were utilized to confirmthe binding ofmiR-22 to the 3' untranslated region (3'-UTR) of galectin-9. The methylation status of miR-22 promoter was analyzed by MSP (Methylation specific PCR) and BSP (bisulfite sequencing PCR), while chromatin immunoprecipitation (ChIP) assay identify the occupation status of EZH2 and H3K27me3 at the promoter. Furthermore, the effect of ectopic expression of galectin-9 and miR-22 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, transwell assays and flow cytometric analysis, respectively. RESULTS:IFN-γ induces up-regulation of galectin-9 and EZH2 in HCC cell lines. Galectin-9 is a target of miR-22 and EZH2 facilitates galectin-9 expression by tri-methylation of H3K27 on miR-22 promoter but not hyper-methylation status of DNA. MiR-22 overexpression suppressed HCC cell growth, invasion, and metastasis both in vitro and in vivo. Interestingly, galectin-9 also exhibited antitumor effects, and restoring galectin-9 expression in miR-22 overexpressing cells strengthened its antitumor effects. CONCLUSIONS:These findings indicated that EZH2 facilitates galectin-9 expression by epigenetically repressing miR-22 and that galectin-9, which is known as an immunosuppressant, also functions as a tumor suppressor in HCC.

| S-EPMC5761110 | biostudies-literature

CircRNA GFRA1 promotes hepatocellular carcinoma progression by modulating the miR-498/NAP1L3 axis.

Project description:Circular RNAs (circRNAs) play essential roles in tumorigenesis and tumor progression. CircRNA GFRA1 (circGFRA1) was dysregulated in many cancer samples and acted as an independent marker for prediction of survivals in various cancer patients. However, the functions and molecular mechanisms of circGFRA1 in hepatocellular carcinoma (HCC) remain unclear. We collected 62 HCC tissues and normal adjacent tissues to evaluate the expression of circGFRA1 and the relationship between circGFRA1 expression and HCC patients' survival. We carried out a list of characterization experiments to investigate the roles and underling mechanisms of circGFRA1 and miR-498 in HCC progressions. CircGFRA1 was greatly increased in HCC tissues and cells, and the over-expression of circGFRA1 was intimately related with the advanced clinical stage and poor survival of HCC patients. The expression of circGFRA1 was negatively correlated with the expression of miR-498, but a positive correlation was found between circGFRA1 and NAP1L3 expression in HCC tissues. Silencing circGFRA1 inhibited the growth and invasion of hepatocellular carcinoma. Moreover, miR-498 over-expression or NAP1L3 inhibition could abrogate the oncogene role of circGFRA1 in HCC in vivo. Our findings indicated that circGFRA1 contributed to HCC progression by modulating the miR-498/NAP1L3 axis in HCC.

| S-EPMC7801409 | biostudies-literature

Circular RNA circ_0000517 regulates hepatocellular carcinoma development via miR-326/IGF1R axis.

Project description:Background:Circular RNAs (circRNAs) play vital roles in hepatocellular carcinoma development. However, the role and mechanism of circRNA hsa_circ_0000517 (circ_0000517) in hepatocellular carcinoma development were largely unknown. Methods:45 paired tumor and adjacent nontumor samples were collected from hepatocellular carcinoma patients. The levels of circ_0000517, miR-326 and insulin-like growth factor type 1 receptor (IGF1R) were detected via quantitative reverse transcription polymerase chain reaction or western blot. Cell viability, colony ability, migration, invasion and glycolysis were assessed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, western blot, transwell assay, glucose consumption, lactate production or adenosine triphosphate (ATP) production. The target correlation between miR-326 and circ_0000517 or IGF1R was analyzed via dual-luciferase reporter analysis. The function of circ_0000517 in vivo was assessed via xenograft model. Results:circ_0000517 expression was elevated in hepatocellular carcinoma tissues and cell lines. circ_0000517 knockdown suppressed cell viability, colony formation, migration, invasion and glycolysis. miR-326 was sponged via circ_0000517 and miR-326 knockdown reversed the effect of circ_0000517 silence on hepatocellular carcinoma development. miR-326 overexpression inhibited hepatocellular carcinoma development through targeting IGF1R. circ_0000517 knockdown decreased IGF1R expression by modulating miR-326. circ_0000517 downregulation reduced xenograft tumor growth. Conclusion:circ_0000517 knockdown repressed hepatocellular carcinoma development in vitro and in vivo by modulating miR-326 and IGF1R.

| S-EPMC7448484 | biostudies-literature

Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis.

Project description:The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-?-induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo. Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC.

| S-EPMC5731931 | biostudies-literature

A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination.

Project description:The presence of invasion into the extra-hepatic portion of the portal vein or the development of distant metastases renders hepatocellular carcinoma (HCC) patients ineligible for the only potential curative options for this malignancy-tumor resection or organ transplantation. Gene expression profiling of murine HCC cell lines identified KLF6 as a potential regulator of HCC cell migration. KLF6 knockdown increases cell migration, consistent with the correlation between decreased KLF6 mRNA levels and the presence of vascular invasion in human HCC. Concordantly, single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs and decreased survival, indicating that KLF6 suppresses both HCC development and metastasis. By combining gene expression profiling and chromatin immunoprecipitation coupled to deep sequencing, we identified novel transcriptional targets of KLF6 in HCC cells including VAV3, a known activator of the RAC1 small GTPase. Indeed, RAC1 activity is increased in KLF6-knockdown cells in a VAV3-dependent manner, and knockdown of either RAC1 or VAV3 impairs HCC cell migration. Together, our data demonstrate a novel function for KLF6 in constraining HCC dissemination through the regulation of a VAV3-RAC1 signaling axis.

| S-EPMC4985511 | biostudies-literature

The ASH1-miR-375-YWHAZ Signaling Axis Regulates Tumor Properties in Hepatocellular Carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a worldwide malignance, and the underlying mechanisms of this disease are not fully elucidated. In this study, the existence and function of achaete-scute homolog-1 (ASH1)-miR-375-YWHAZ signaling axis in HCC were determined. Our experiments and the Cancer Genome Atlas (TCGA) sequencing data analyses showed that ASH1 and miR-375 were significantly downregulated, whereas YWHAZ was significantly upregulated in HCC. Furthermore, we found that ASH1 positively regulates miR-375, and miR-375 directly downregulates its target YWHAZ. Gain- and loss-of-function study demonstrated ASH1 and miR-375 function as tumor suppressors, whereas YWHAZ acts as an oncogene in HCC. Animal experiment indicated that YWHAZ small interfering RNAs (siRNAs) (si-YWHAZ) delivered by nanoliposomes could suppress the growth of hepatoma xenografts and was well tolerant by nude mice. Further studies revealed that YWHAZ was involved in several protein networks, such as cell autophagy, epithelial-mesenchymal transition (EMT), apoptosis, cell cycle, invasion, and migration. In addition, the patient group with ASH1-high-expression-miR-375-high-expression-YWHAZ-low-expression was correlated with a better clinical prognosis compared with the opposite expression group. In conclusion, we proved the existence of ASH1-miR-375-YWHAZ signaling axis and interpreted its important role in driving HCC tumor progression.

| S-EPMC5944419 | biostudies-literature

LINC00346 Acts as a Competing Endogenous RNA Regulating Development of Hepatocellular Carcinoma via Modulating CDK1/CCNB1 Axis.

Project description:Hepatocellular carcinoma (HCC) is one of the important types of liver cancer. LncRNA is an important regulatory factor that regulates many biological processes such as tumor cells during tumorigenesis and metastasis. LINC00346 has been associated with various types of liver cancer, but its role and regulatory mechanism in HCC remain unclear. In our study, we found the LINC00356-miR-199a-3p-CDK1/CCNB1 axis through bioinformatics analysis. The expressions of LINC00356, miR-199a-3p, CDK1, and CCNB1 in HCC and normal hepatocytes were determined by qRT-PCR and WB. The results showed that LINC00356, CDK1 and CCNB1 were highly expressed in HCC, while miR-199a-3p was lowly expressed. Dual luciferase reporter gene assay, RIP and RNA-pull down assays demonstrated the targeted binding relationship of LINC00346-miR-199a-3p-CDK1/CCNB1. Overexpressing LINC00460 and silencing miR-199a-3p promoted cell invasion, inhibited apoptosis of HCC, and arrested the cell cycle in S phase while opposite results were obtained when silencing LINC00346, CDK1, and CCNB1. LINC00346 indirectly affects liver cancer by promoting the expression of CDK1/CCNB1 through competitive adsorption of miR-199a-3p. In addition, the study also demonstrated that overexpression of LINC00346 indirectly inhibited the expression of p53 and p21 proteins by promoting CDK1/CCNB1 expressions, thereby blocking the p53 signaling pathway. These results proved that LINC00346 could regulate the expression of CDK1/CCNB1 through the competitive adsorption of miR-199a-3p, thereby affecting the p53 signaling pathway and finally regulating the apoptosis, invasion and cell cycle of HCC cells. In conclusion, LINC00346 can be used as a tumor promoter and potential therapeutic target for HCC metastasis and prognosis.

| S-EPMC7039823 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data