Melatonin attenuates hypoxia-induced epithelial-mesenchymal transition and cell aggressive via Smad7/ CCL20 in glioma.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen X
PROVIDER: S-EPMC5706820 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
Melatonin attenuates hypoxia-induced epithelial-mesenchymal transition and cell aggressive via Smad7/ CCL20 in glioma.
Chen Xueran X Wang Zhen Z Ma Huihui H Zhang Shangrong S Yang Haoran H Wang Hongzhi H Fang Zhiyou Z
Oncotarget 20170824 55
Tumor recurrence in gliomas is partly attributed to increased epithelial-mesenchymal transition (EMT) and enhanced tumor cell dissemination in the adjacent brain parenchyma. Thus, exploring effective strategies for against EMT-like changes in glioma invasion and recurrence will be important for glioma treatment. In this study, we investigated the roles of melatonin in hypoxia-induced EMT suppression, and found that melatonin could significantly suppress the release of the cytokine, CCL20, from c ...[more]
Similar Datasets
Project description:C-C motif chemokine ligand 20 (CCL20) participates in multiple oncogenic processes, but its role in lung adenocarcinoma (LUAD) is unclear. Herein, we explored the mechanism by which CCL20 works in LUAD progression. We performed bioinformatical analyses based on the complete transcriptome sequencing data from 1544 LUAD cases in 4 independent cohorts to evaluate signaling pathways regulated by CCL20. We established A549 and H358 cell lines with CCL20 knockdown to explore how CCL20 promotes tumor progression in vitro and in vivo experiments. Using another independent cohort of 348 urothelial carcinoma patients treated with the anti-PD-L1 agent (atezolizumab), we explored the synergistic effect of CCL20 and TGF-β on immunotherapy efficacy. High CCL20 expression is a poor prognostic marker for LUAD patients, and is associated with enhanced epithelial-mesenchymal transition (EMT), inflammatory response, and activated TNF pathway in LUAD. CCL20 knockdown restrained the EMT process and cell proliferation of LUAD cells in vitro and in vivo. Low CCL20 expression blocked the detrimental effects of high TGF-β on survival and effectively improved patients' response to anti-PD-L1 therapy. Collectively, we revealed the underlying mechanisms by which CCL20 promotes LUAD progression based on the largest sample size. The synergistic inhibitory effect of CCL20 and TGF-β on immune-checkpoint blockade therapy efficacy provides new views of immunotherapy resistance.
| S-EPMC9295072 | biostudies-literature
Project description:Background: Epithelial-mesenchymal transition (EMT) is regulated by induction factors, transcription factor families and an array of signaling pathways genes, and has been implicated in the invasion and progression of gliomas. Methods: We obtained the Clinicopathological data sets from Chinese Glioma Genome Atlas (CGGA). The "limma" package was used to analyze the expression of EMT-related genes in gliomas with different pathological characteristics. We used the "ConsensusClusterPlus" package to divide gliomas into two groups to study their correlation with glioma malignancy. The least absolute shrinkage and selection operator (LASSO) Cox regression was applied to select seven prognosis-associated genes to build the risk signature, and the coefficients obtained from the LASSO algorithm were used to calculate the risk score which we applied to determine the prognostic value of the risk signature. Univariate and multivariate Cox regression analyses were used to determine whether the risk signature is an independent prognostic indicator. Results: We analyzed the differentially expressed 22 common epithelial-mesenchymal transition-associated genes in 508 gliomas graded by different clinicopathological features. Two glioma subgroups (EM1/2) were identified by consistent clustering of the proteins, of which the EM1 subgroup had a better prognosis than the EM2 subgroup, and the EM2 group was associated with cancer migration and proliferation. Significant enrichment analysis revealed that EMT-related transcriptional regulators and signaling pathways genes were highly related to glioma malignancies. Seven EMT-related genes were used to derive risk scores, which served as independent prognostic markers and prediction factors for the clinicopathological features of glioma. And we found the overall survival (OS) was significantly different between the low- and high-risk groups, the ROC curve indicated that the risk score can predict survival rates for glioma patients. Conclusion: EMT-related induction factors, transcriptional regulators and signaling pathways genes are important players in the malignant progression of glioma and may help in decision making regarding the choice of prognosis assessment and provide us clues to understand EMT epigenetic modification in glioma.
| S-EPMC7047417 | biostudies-literature
Project description:Long intergenic noncoding RNA smad7 (Linc-smad7) has been recently identified as a new long non-coding RNA (lncRNA). However, the role of Linc-smad7 in the tumourigenesis of human cancers remains unknown. This study uncovered that Linc-smad7 was increased in HCC samples and HCC cell lines using RT-qPCR assays. Furthermore, the overexpression of Linc-smad7 indicated poor clinicopathological features and outcomes for HCC patients. In addition, Linc-smad7 promoted HCC cells proliferation, migration, invasion and EMT, as determined by MTT, colony formation, Transwell assays and western blot analysis. Functionally, it was demonstrated that Linc-smad7 could bind with microRNA-125b (miR-125b), and the restoration of miR-125b rescued the promoting effects of Linc-smad7 on HCC cells. Finally, it was observed that sirtuin 6 (SIRT6) was positively regulated by Linc-smad7 in HCC as the direct target of miR-125b, and decreased SIRT6 reversed the effects of Linc-smad7 on promoting HCC. In conclusion, the current study first identified Linc-smad7 is increased in HCC, facilitating HCC cells proliferation, migration, invasion and EMT via regulating the miR-125b/SIRT6 axis.
| S-EPMC7724296 | biostudies-literature
Project description:The epithelial-to-mesenchymal transdifferentiation (EMT) is crucial for tissue differentiation in development and drives essential steps in cancer and fibrosis. EMT is accompanied by reprogramming of gene expression and has been associated with the epithelial stem-cell state in normal and carcinoma cells. The cytokine transforming growth factor β (TGF-β) drives this program in cooperation with other signaling pathways and through TGF-β-activated SMAD3 as the major effector. TGF-β-induced SMAD3 activation is inhibited by SMAD7 and to a lesser extent by SMAD6, and SMAD6 and SMAD7 both inhibit SMAD1 and SMAD5 activation in response to the TGF-β-related bone morphogenetic proteins (BMPs). We previously reported that, in response to BMP, protein arginine methyltransferase 1 (PRMT1) methylates SMAD6 at the BMP receptor complex, thereby promoting its dissociation from the receptors and enabling BMP-induced SMAD1 and SMAD5 activation. We now provide evidence that PRMT1 also facilitates TGF-β signaling by methylating SMAD7, which complements SMAD6 methylation. We found that PRMT1 is required for TGF-β-induced SMAD3 activation, through a mechanism similar to that of BMP-induced SMAD6 methylation, and thus promotes the TGF-β-induced EMT and epithelial stem-cell generation. This critical mechanism positions PRMT1 as an essential mediator of TGF-β signaling that controls the EMT and epithelial cell stemness through SMAD7 methylation.
| S-EPMC6109915 | biostudies-literature
Project description:Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial-mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT-related markers including E-cadherin, N-cadherin, Vimentin, Snail, and Slug, transforming growth factor β (TGF-β) signaling pathway including Smad2/3, p-Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual-luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N-cadherin, Vimentin, Snail, Slug, TGF-β signaling pathway and negatively correlated with the expression of E-cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF-β signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-β signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC.
| S-EPMC9807500 | biostudies-literature
Project description:BackgroundHypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer.MethodsFour breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment.ResultsExposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P=0.048).ConclusionsOur results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.
| S-EPMC2778529 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-β1-induced model and an in vivo bleomycin (BLM)-induced model.MethodsIn vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-β1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-β1, E-cadherin (E-cad), and α-smooth muscle actin (SMA) in lung tissues.ResultsSFN reversed mesenchymal-like changes induced by TGF-β1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and α-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-β1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-β1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and α-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-β1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-β1 expression, and the levels of collagen I in the lungs of mice.ConclusionsSFN showed a significant anti-fibrotic effect in TGF-β-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.
| S-EPMC5879815 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) cannot be treated with current hormonal therapies and has a higher risk of relapse than other breast cancers. To identify potential therapeutic targets for TNBC, we conducted microRNA sequencing (RNA-Seq) in human TNBC specimens and tumor-matched controls. We found that growth differentiation factor-10 (GDF10), a member of the TGF-β superfamily, was downregulated in tumor samples. Further analysis of GDF10 expression in a larger set of clinical TNBC samples using qPCR confirmed its downregulation and association with parameters of disease severity. Using human-derived TNBC cell lines, we carried out GDF10 under- and overexpression experiments, which showed that GDF10 loss promoted cell proliferation and invasion. By contrast, overexpression of GDF10 inhibited proliferation, invasion, and epithelial mesenchymal transition (EMT) via upregulation of Smad7 and E-Cadherin, downregulation of p-Smad2 and N-Cadherin, and reduction of nuclear Smad4 expression. In addition, overexpression of GDF10 reduced tumor burden and induced apoptosis in a TNBC xenograft mouse model. These findings indicate that GDF10 acts as a tumor suppressor in mammary epithelial cells that limits proliferation and suppresses EMT. Efforts aimed at restoring GDF10 expression may thus bring a long-sought therapeutic alternative in the treatment of patients with TNBC.
| S-EPMC6555447 | biostudies-literature
Project description:The transforming growth factor β (TGFβ) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGFβ signalling, thus mediating a negative feedback loop that may potentially restrain TGFβ responses of cancer cells. Here, however, we show that TGFβ treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFβ activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGFβ treatment and prevents TGFβ-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFβ-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGFβ self-restraint and provide a mechanism to explain the unleashed TGFβ responses in metastatic cancer cells.
| S-EPMC5187443 | biostudies-literature
Project description:BackgroundTo observe the effects of triptolide (TP) on the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of glioma cells, and to explore the possible mechanisms of phenotypic changes in EMT.MethodsThe U87 and U251 glioma cell lines were treated TP. The Cell Counting Kit-8 (CCK-8) method was used to detect the half-maximal inhibitory concentration (IC50) of TP in these two cell lines and the inhibition of cell proliferation at the IC50 concentration. The wound-healing experiment and Transwell invasion assay were used to detect the cells' migration and invasion abilities, respectively. Using western blot protocol, the expression levels of the EMT markers were analyzed, and the levels of the autophagy markers were also detected. The pEGFP-C2-LC3B plasmid was transfected into glioma cells, and the effect of TP on autophagy was detected by immunofluorescence. A subcutaneous tumor model in nude mice was established to observe the effect of TP on cell proliferation in vivo, and immunohistochemistry (IHC) was used to detect the expression levels of EMT markers in mouse tumor tissues.ResultsTP significantly inhibited the proliferation of U87 and U251 cells in a dose- and time-dependent manner. TP had a significant inhibitory effect on the migration and invasion of U87 and U251 cells. Western blot showed that TP reversed the process of EMT in glioma cells, which was evidenced by the upregulated expression of the epithelial marker E-cadherin, and the downregulated expression of the mesenchymal markers N-cadherin, Vimentin, ZEB1, Snail, and Slug. TP increased autophagy in glioma cells, increased the LC3B II/I ratio, and upregulated Beclin-1 and Atg-7 expression. Immunofluorescence showed that the number of autophagosomes increased significantly after TP was applied to cells. In the nude mouse subcutaneous tumor model, experiments revealed an inhibitory effect of TP on glioma cell proliferation in vivo. IHC confirmed that the expression of E-cadherin was upregulated in mouse tumor tissues, while the expression levels of N-Cadherin and Vimentin were downregulated.ConclusionsTP can inhibit glioma cell proliferation, migration, and invasion, and reverse EMT progression. The possible mechanism of EMT reversal in glioma cells is that TP induces autophagy.
| S-EPMC8422147 | biostudies-literature