NF-κB-Dependent Snail Expression Promotes Epithelial-Mesenchymal Transition in Mastitis.
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ABSTRACT:
SUBMITTER: Liu H
PROVIDER: S-EPMC8698035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. However, neither mechanisms nor the role that LCN2 plays in the metastasis of colorectal cancer are clear.MethodsLCN2 expression in colorectal cancer was detected by immunohistochemistry in 400 tissue specimens and Kaplan-Meier survival analysis was performed. In vitro, real-time PCR, western blot, colony formation assay, immunofluorescence assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LCN2 in epithelial mesenchymal transition (EMT), migration and invasion, respectively. In vivo mouse xenograft and metastasis models were utilized to determine tumorigenicity and metastasis ability, and immunohistochemistry, real-time PCR, western blot were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of LCN2 on NF-ĸB promoter.ResultsLCN2 was highly expressed in 66.5% of the specimens, and significantly correlated with positive E-cadherin in the membrane and negative nuclear β-catenin. Higher expression of LCN2 together with negative NF-κB expression was negatively related to nuclear accumulation of snail and predicted favorable prognosis. LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into nucleus. NF-κB could reverse the effect of LCN2 on EMT and promote snail expression. Rescued snail expression had similar effect without influencing NF-κB activity.ConclusionLCN2 may be an important negative regulator in EMT, invasion and metastasis of CRC via acting as upstream of NF-κB/snail signaling pathway. Thereby combinative manipulation of LCN2 and NF-κB/snail pathway may represent a novel and promising therapeutic approach for the patients with CRC.
| S-EPMC5135816 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and with poor prognosis. In this study, we demonstrate the key role of RPB5-mediating protein (RMP) in EMT of HCC cells and the mechanism by which RMP promote EMT. RMP increases migration, invasion, and the progress of EMT of HCC cells, which facilitates the accumulation of Snail, a transcriptional repressor involved in EMT initiation. NF-?B is activated by RMP, which directly promotes the expression of COP9 signalosome 2 (CSN2) to repress the degradation of Snail. Pulmonary metastases mouse model demonstrates that RMP induces metastasis in vivo. Immunohistochemical analysis of human HCC tissues confirms the correlation of RMP with the expression of E-cadherin, p65, CSN2 and Snail in vivo. Collectively, these findings indicate that RMP promotes EMT and HCC metastasis through NF-?B/CSN2/Snail pathway. These results suggest that RMP and p65 may serve as potential candidates of the targets in the treatment of metastatic HCC.
| S-EPMC5522250 | biostudies-literature
Project description:Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-κB/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-β challenge in a mouse model. These data provide a detailed mechanism for how activated NF-κB and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.
| S-EPMC5206405 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is characterized by loss of cell-cell junctions, polarity and epithelial markers, and in turn, acquisition of mesenchymal features and motility. Changes associated with this developmental process have been extensively implicated in breast cancer progression and metastasis. Matrix metalloproteinases (MMPs) have been identified as specific inducers of EMT in mammary epithelial cells. MMP-3 induces EMT associated with malignant transformation via a pathway dependent upon production of reactive oxygen species (ROS). While the process by which exposure to MMP-3 leads to induction of ROS has been extensively studied, exactly how the MMP-3-induced ROS stimulate EMT remains unknown. Here, we used profiling methods to identify MMP-3-induced transcriptional alterations in mouse mammary epithelial cells, finding common overlap with changes mediated by nuclear factor-?B (NF-?B) and found in advanced breast cancer. In cultured cells, we found that Snail, an ROS-dependent key mediator of MMP-3-induced changes, is regulated by NF-?B in response to MMP-3. More specifically, we found MMP-3 to cause binding of p65 and cRel NF-?B subunits to the Snail promoter, leading to its transcription. Our results identify a specific pathway by which MMPs induce EMT and malignant characteristics, and provide insight into potential therapeutic approaches to target MMP-associated breast cancers.
| S-EPMC4058048 | biostudies-literature
Project description:RUFY3 (RUN and FYVE domain-containing protein 3) has been demonstrated to exhibit carcinogenic effect in multiple malignancies. However, the exact role of RUFY3 in hepatocellular carcinoma (HCC) progression remains elusive. Herein, we aimed to identify the role and the underlying mechanism of RUFY3 in HCC progression. The RUFY3 levels in HCC specimens were detected by qRT-PCR, western blot, and immunohistochemistry, and its clinical significance in HCC patients was assessed. The effect of RUFY3 on HCC cell growth, migration, and invasion was explored by CCK-8 assay, wound healing assay, and transwell migration and invasion assays in vitro. The effect of RUFY3 on HCC cell growth and metastasis was also conducted in vivo through establishing xenograft tumor and lung metastatic mice model. The underlying mechanism responsible for RUFY3-induced HCC cell behavior was also investigated. Our results indicated that high levels of RUFY3 significantly correlated with tumor size, microvascular invasion, clinical stage, and poor prognosis for HCC patients. In addition, RUFY3 facilitated HCC cell growth, invasion, and metastasis both in vitro and in vivo through activating nuclear factor-κ-gene binding (NF-κB)-mediated epithelial-mesenchymal transition (EMT). Taken together, our results revealed that RUFY3 accelerated HCC progression via driving NF-κB-mediated EMT, suggesting a novel target for HCC treatment.
| S-EPMC8457573 | biostudies-literature
Project description:Background:Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. Emerging evidence indicates that hyperglycemia promotes tumor progression, especially the processes of migration, invasion and epithelial-mesenchymal transition (EMT). However, the underlying mechanisms of GC remain unclear. Method:Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to detect the expression of glycolysis-related enzymes and EMT-related transcription factors. Small interfering RNA (siRNA) transfection was performed to decrease ENO1 expression. Immunohistochemistry (IHC), Western blot and qRT-PCR analyses were used to measure gene expression at the protein or mRNA level. CCK-8, wound-healing and Transwell assays were used to assess cell proliferation, migration and invasion. Results:Among the glycolysis-related genes, ENO1 was the most significantly upregulated in GC, and its overexpression was correlated with poor prognosis. Hyperglycemia enhanced GC cell proliferation, migration and invasion. ENO1 expression was also upregulated with increasing glucose concentrations. Moreover, decreased ENO1 expression partially reversed the effect of high glucose on the GC malignant phenotype. Snail-induced EMT was promoted by hyperglycemia, and suppressed by ENO1 silencing. Moreover, ENO1 knockdown inhibited the activation of transforming growth factor ? (TGF-?) signaling pathway in GC. Conclusions:Our results indicated that hyperglycemia induced ENO1 expression to trigger Snail-induced EMT via the TGF-?/Smad signaling pathway in GC.
| S-EPMC6924061 | biostudies-literature
Project description:We aimed to explore the role and mechanism of SOS1 (Son of sevenless homolog 1) in malignant behaviors of epithelial ovarian cancer (EOC) cells Hey with high metastatic potential. Firstly, compared with Hey-WT (wild type) and Hey-NT (none targeted) cells, Hey-SOS1i cells showed decreased polarities, disorders in cytoskeleton arrangement. Numbers of transwell migrated, invaded, intravasation cells and extravasated cells were decreased significantly. Hey-NT cells and Hey-SOS1i cells were employed to establish a peritoneal dissemination model in nude mice. Hey-SOS1i cells formed less implantation metastatic foci in the abdominal cavity than Hey-NT cells, especially on the intestine and diaphragm in the 5th week after the tumor cells were injected intraperitoneally. SOS1 knockdown in Hey cells resulted in increased E-cadherin and decreased Vimentin, N-cadherin, MMP2, and MMP9, together with reduced Snail and activation of NF-κB pathway. Together, these results suggest SOS1 might induce EMT through activating AKT independent NF-κB pathway and the transcriptive activity of Snail, and subsequently regulate the cytoskeleton reprogramming and cell motility of Hey, one of EOC cells with high metastatic potential. This may provide some new targets for the treatment of ovarian cancer with high metastatic potential.
| S-EPMC8242062 | biostudies-literature
Project description:PurposeSurgical resection is considered as a curative treatment modality for hepatocellular carcinoma; however, the incidence of postoperative tumor recurrence is high, leading to worse patient survival. Persistent hepatitis (inflammation) is one of the risk factors of tumor recurrence after surgical resection. The aim of this study is to investigate the underlying mechanisms linking liver inflammation to hepatocellular carcinoma progression.Experimental designIn this study, we used a cytokine array to identify important cytokines whose levels are increased in liver microenvironment with severe hepatitis. We evaluated the morphologic changes, migration and invasion ability, and signal transduction in hepatocellular carcinoma cells with or without inflammatory cytokine in vitro Finally, we analyzed the NF-κB signal pathway in tumor specimens from 232 patients with hepatocellular carcinoma by immunohistochemical staining.ResultsThe proinflammatory cytokine TNFα was increased in the peritumoral microenvironment and contributed to tumor recurrence and metastasis. Specifically, TNFα promoted hepatocellular carcinoma cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) by upregulating the transcriptional regulator, Snail. We identified Snail as a direct target gene downstream of the TNFα-mediated canonical NF-κB activation. In addition, tumor recurrence-free survival of hepatocellular carcinoma patients correlated negatively with high p65 and Snail expression and positively with high E-cadherin expression.ConclusionsOur results establish a signaling axis that explains how inflammatory tumor microenvironment promotes hepatocellular carcinoma recurrence and metastasis. These findings suggest that controlling liver inflammation and/or targeting NF-κB-mediated Snail expression may be a potential therapeutic strategy to prevent hepatocellular carcinoma recurrence after hepatectomy.
| S-EPMC4818680 | biostudies-literature
Project description:BackgroundMetastasis accounts for the most deaths in patients with hepatocellular carcinoma (HCC). Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown.MethodsImmunohistochemistry was performed to determine the expression of RANK in HCC tissue (n = 398). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to examine the expression of RANK, E-cadherin, N-cadherin, vimentin, Snail, Slug, Twist and MMPs in HCC cells. Wound healing and Transwell assays were used to evaluate cell migration and invasion ability.ResultsWe found that expression of RANK, the receptor of RANKL, was significantly higher in HCC tumor tissues than in peritumor liver tissues (p<0.001). Constitutive expression of RANK was detected in HCC cell lines, which can be up-regulated when HCC cells were stimulated with RANKL. Notably, in vitro experiments showed that activation of RANKL-RANK axis significantly promoted migration and invasion ability of HCC cells. In addition, RANKL stimulation increased the expression levels of N-cadherin, Snail, and Twist, while decreased the expression of E-cadherin, with concomitant activation of NF-κB signaling pathway. Moreover, administration of the NF-κB inhibitor attenuated RANKL-induced migration, invasion and epithelial-mesenchymal transition of HCC cells.ConclusionsRANKL could potentiate migration and invasion ability of RANK-positive HCC cells through NF-κB pathway-mediated epithelial-mesenchymal transition, which means that RANKL-RANK axis could be a potential target for HCC therapy.
| S-EPMC4182493 | biostudies-literature
Project description:There are limited reports with respect to the study on the epithelium-mesenchymal transformation (EMT) mediated by Snail in the ovarian cancer. This study detected the expression of Snail and related EMT markers in the ovarian cancer tissues, and explored the possible molecular mechanism of EMT mediated by Snail in the metastasis of ovarian cancer. The patients diagnosed with ovarian cancer according to the pathology were recruited in this study during 2010-2014. The carcinoma tissue and normal tissue adjacent to carcinoma were surgically obtained from patients. The genes of E-cadherin, ?-catenin, Fibronectin and N-cadherin were detected using the RT-PCR. The 64 patients were recruited and diagnosed as ovarian cancer by pathological examination. The expression levels of Snail, Fibronectin and N-cadherin in the stage III and IV were higher than those in the stage I and II, respectively (all P < 0.05). However, the expression levels of E-cadherin and ?-catenin decreased along with the stage developed (trend test, both P < 0.05), respectively. The expression of Snail was positively correlated with the expression of Fibronectin, N-cadherin, but negatively correlated with the expression of E-cadherin and ?-catenin. The number of A2780 cells entering into the lower compartment in the group of carcinoma tissue were significantly higher than that in the group of normal tissue after transfected with Snail expression vector. While, the invasion ability of A2780 significantly reduced after RNAi-Snail. The correlation between Snail and invasion and metastasis of ovarian cancer and epithelial-mesenchymal transition based on tissue and cell levels, and to some extent explored the molecular mechanism of the EMT process mediated by Snail.
| S-EPMC4509225 | biostudies-literature