AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)ce...AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.展开更多
Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles o...Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles of human alveolar type II epithelial cells(A549 cells)exposed directly to silica were characterized using non-targeted metabolomic approaches.A total of 84 differential metabolites(DMs)were identified in silica-treated A549 cells undergoing EMT,which were mainly enriched in metabolisms of amino acids(e.g.,glutamate,alanine,aspartate),purine metabolism,glycolysis,etc.The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica.Remarkably,glutamine catabolism was significantly promoted in the silica-treated A549 cells,and the levels of related metabolites(e.g.,succinate)and enzymes(e.g.,α-ketoglutarate(α-KG)dehydrogenase)were substantially up-regulated,with a preference toα-KG pathway.Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail(zinc finger transcription factor).Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.展开更多
BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progr...BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.展开更多
Background:Colorectal cancer(CRC)is common and deadly,often leading to metastasis,challenging treatment,and poor outcomes.Understanding its molecular basis is crucial for developing effective therapies.Aims:This study...Background:Colorectal cancer(CRC)is common and deadly,often leading to metastasis,challenging treatment,and poor outcomes.Understanding its molecular basis is crucial for developing effective therapies.Aims:This study aimed to investigate the role of Myosin Heavy Chain 11(MYH11)in CRC progression,especially its effects on epithelial-mesenchymal transition(EMT)and cell behavior,and to explore its potential regulation by the EMT transcription factor zinc finger E-box binding homeobox 1(ZEB1).Methods:Differential expression analysis was performed in the GSE123390 and TCGA-READ datasets,and 317 intersection genes were identified.The hub gene MYH11 was identified based on Protein-protein interaction(PPI)analysis and expression validation.The effects of MYH11 and the EMT transcription factor(ZEB1)on the behavior of CRC cells were investigated in vitro.Results:Bioinformatics research revealed that MYH11 was considerably downregulated in CRC samples as compared to normal samples.Overexpression of MYH11 inhibited the proliferation,migration,and invasion of CRC cells.Western blotting(WB)testing showed that MYH11 overexpression inhibited EMT by elevating E-cadherin levels while suppressing ZEB1,vimentin,and N-cadherin expressions.By contrast,overexpression of ZEB1 promoted EMT and enhanced migration,invasion,and proliferation of CRC cells.The negative impacts of MYH11 affecting EMT markers and cell behaviors were partially mitigated by co-overexpression of MYH11 and ZEB1,indicating that MYH11 regulates EMT and CRC progression through ZEB1.Conclusion:Our study shows MYH11 curbs CRC growth by blocking EMT and invasion,but ZEB1 overexpression reduces this effect.It uncovers key CRC pathways and suggests MYH11’s therapeutic potential.展开更多
Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic ne...Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic nephropathy(DN).Rhein is the main active anthraquinone derivative in several common traditional herbal medicines.This study aimed to investigate the protective effects of Rhein on podocyte ferroptosis and EMT.Methods:The mouse glomerular podocyte cell line MPC5 was stimulated with high glucose(HG),Rhein,and the ferroptosis inhibitor ferrostatin-1(Fer-1).Mechanistic investigations employed plasmids to overexpress and knockdown Sirtuin-1(SIRT1),solute carrier family 7 member 11(SLC7A11),or p53 and measure ferroptosis-or EMT-related indicators.Results:In the HG-injured podocytes,Rhein enhanced cell viability,reduced malondialdehyde(MDA),ferrous iron(Fe2+),and reactive oxygen species(ROS)levels,increased glutathione(GSH)production,accompanied by the restoration of ferroptosis-and EMT-associated indicator expressions.Mechanistically,Rhein induced SIRT1 and SLC7A11 expression and attenuated p53 expression.SIRT1 knockdown upregulated p53 and downregulated SLC7A11,thereby abolishing the protective effects of Rhein against podocyte ferroptosis and EMT.However,the effects of SIRT1 overexpression were reversed by SLC7A11 knockdown.Conclusion:Rhein activated the SIRT1/p53/SLC7A11 axis to protect podocytes against ferroptosis and EMT.This suggests that Rhein has a potential therapeutic effect on DN patients associated with podocyte injury,and targeting SIRT1/p53/SLC7A11 may represent an innovative therapeutic strategy for DN patients.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in v...BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in vivo,with the objective of identifying novel diagnosis and treatment targets for HCC.METHODS The expression of TMC in cancer and normal tissues,along with its correlation with HCC prognosis,was analyzed using the GENT2,GEPIA database,and Human Protein Atlas.COX analysis was conducted to assess the relationship between TMC5 expression and overall survival in TCGA-LIHC patients.Further experiments were conducted to investigate the effect of TMC5 in cancer progression through loss-and gain-of-function assays in vitro and in vivo.RESULTS Bioinformatics revealed that TMC5 expression was generally higher in tumors than in normal tissues,and its expression was associated with poorer patient survival outcomes.TMC5 expression in HCC tissues and cells was consistent with the results of the bioinformatics analysis.Suppression of TMC5 expression reduced migration,invasion,and proliferation,while also decreasing the expression of epithelial-mesenchymal transition(EMT)-associated molecules in MHCC97-LM3 cells.Conversely,higher TMC5 expression significantly increased cell migration,invasion,proliferation,and EMT in MHCC97 L cells.TMC5 knockdown significantly decreased both the formation and spread of nodules in liver tissue,whereas TMC5 overexpression promoted them.CONCLUSION Our study provides compelling evidence that TMC5 is highly expressed in HCC and drives cancer progression through the activation of EMT-mediated invasion.TMC5 could represent a valuable molecular target for the diagnosis and treatment of HCC.展开更多
BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identify...BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.展开更多
Circular RNAs(circRNAs)are formed by splicing of precursor RNAs and covalently linked at the 5′and 3′ends.Dysregulated circRNAs are closely related to the epithelial-mesenchymal transition(EMT)of gastrointestinal ma...Circular RNAs(circRNAs)are formed by splicing of precursor RNAs and covalently linked at the 5′and 3′ends.Dysregulated circRNAs are closely related to the epithelial-mesenchymal transition(EMT)of gastrointestinal malignancies.CircRNAs,including circRNA_0008717,circGOT1,circ-DOCK5,circVPS33B,circPVT1,circMET,circ-OXCT1,circ_67835,circRTN4,circ_0087502,circFNDC38,circ_PTEN1,circPGPEP1,and circ-E-Cad are involved in the EMT process of gastrointestinal malignancies through a variety of mechanisms,such as regulating EMT-inducing transcription factors,signaling pathways,and tumor microenvironments.Gastrointestinal(GI)malignancies are common malignant tumors worldwide,and the heterogeneity and easy metastasis of gastrointestinal malignancies limit the effectiveness of medical treatments.Therefore,investigating the molecular mechanisms involved in the pathogenesis of gastrointestinal malignancies is essential for clinical treatment.This article summarizes the biological roles and molecular mechanism of circRNAs in EMT of gastrointestinal malignancies,providing a theoretical basis for applying EMT-related circRNAs in targeted therapy.展开更多
BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous...BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.展开更多
BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies hav...BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.展开更多
Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing ...Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.展开更多
BACKGROUND Helicobacter pylori(H.pylori)infection is widely considered to be a major risk factor for gastric cancer,contributing to its development through the Correa cascade.Yin Yang 1(YY1)is a transcription factor t...BACKGROUND Helicobacter pylori(H.pylori)infection is widely considered to be a major risk factor for gastric cancer,contributing to its development through the Correa cascade.Yin Yang 1(YY1)is a transcription factor that acts as a promoter or suppressor of cancer progression.However,the role of YY1 in the inflammatory transformation associated with H.pylori-induced gastric cancer remains unclear.AIM To explore the expression of YY1 in gastric cancer and its impact on cancer progression with H.pylori infection.METHODS H.pylori bacteria were cocultured with GSE1 cells,AGS cells,and SGC7901 cells,as well as in infected and xenograft mouse models.Expression of YY1,members of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway,and epithelial-mesenchymal transition(EMT)-related proteins in gastric cancer was examined using Western blotting,quantitative realtime polymerase chain reaction,and immunohistochemistry.Survival analysis was performed using the Kaplan-Meier method with the log-rank test.The role of YY1 in gastric cancer cell proliferation was further evaluated through in vitro and in vivo assays.RESULTS YY1 was highly expressed in gastric cancer tissues and cells.Kaplan-Meier survival curves indicated that high YY1 expression correlated with a poor prognosis.YY1 expression showed a gradually increasing trend in H.pyloriinduced gastritis and gastric tumors.In vivo and in vitro experiments demonstrated that H.pylori infection promoted phosphorylation of JAK2 and STAT3,thereby activating the EMT pathway,in which YY1 played a key role.YY1 and JAK2 interaction was validated by chromatin immunoprecipitation.YY1 knockdown or pharmacological inhibition reversed EMT and suppressed gastric cancer cell proliferation and metastasis.CONCLUSION These results suggest that YY1 plays an important role in progression of H.pylori-induced gastric cancer by activating EMT.展开更多
Objective: Epithelial-mesenchymal transition (EMT) is a critical early event for the invasion and metastasis of many carcinomas. In the present study, we examined EMT markers in the residual cancer cells of hepatocell...Objective: Epithelial-mesenchymal transition (EMT) is a critical early event for the invasion and metastasis of many carcinomas. In the present study, we examined EMT markers in the residual cancer cells of hepatocellular carcinoma (HCC) after radiotherapy. Methods: Eight patients with large HCC who underwent hepatectomy with preoperative radiothera- py were studied. The expressions of E-cadherin and vimentin were determined immunohistochemically in the residual cancer cells of HCC following radiotherapy, and also in the pre-radiotherapy biopsy cancer cells. Results: Histological analysis showed that some residual cancer cells of HCC displayed an elongated spindle or fibroblast-like shape. The expression of E- cadherin was markedly reduced or negative in the spindle residual cancer cells, but the expression of vimentin significantly in- duced. However, the above changes were not found in the pre-radiotherapy biopsy cancer cells. Conclusion: EMT is induced in the residual cancer cells of HCC following radiotherapy, which may facilitate the systemic dissemination of cancer cells.展开更多
Objective:To study the correlation of Claudins6 (CLDN6) gene expression in meningioma tissue with the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of matrix metalloproteinase (TIMPs) and epithelial...Objective:To study the correlation of Claudins6 (CLDN6) gene expression in meningioma tissue with the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of matrix metalloproteinase (TIMPs) and epithelial-mesenchymal transition (EMT) genes.Methods:Meningioma tissue samples that were surgically removed in Yibin First People's Hospital between April 2014 and May 2017 were selected, normal arachnoid tissue samples that were collected from decompressive craniectomy in Yibin First People's Hospital during the same period were selected, and the expression of CLDN6, MMPs/TIMPs and EMT genes in tissues were determined.Results: CLDN6 protein expression in meningioma tissue was significantly lower than that in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue were significantly higher than those in normal arachnoid tissue while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly lower than those in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue with higher CLDN6 expression were significantly lower than those in meningioma tissue with lower CLDN6 expression while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly higher than those in meningioma tissue with lower CLDN6 expression. Conclusion: Lowly expressed CLDN6 gene in meningioma tissue can increase the hydrolysis activity of MMPs, induce epithelial-mesenchymal transition and thus promote the invasive growth of meningioma.展开更多
Background:Epithelial-mesenchymal transition(EMT) is believed to be the critical process in malignant tumor invasion and metastases,and has a great influence on improving the survival rate in non-small-cell lung cance...Background:Epithelial-mesenchymal transition(EMT) is believed to be the critical process in malignant tumor invasion and metastases,and has a great influence on improving the survival rate in non-small-cell lung cancer(NSCLC) patients.Recent studies suggested that eukaryotic initiation factor 5A-2(eIF5A-2) might serve as an adverse prognostic marker of survival.We detected eIF5A-2 in NSCLC A549 cells,and found that the invasive capability correlates with the eIF5A-2 expression.Methods:Transforming growth factor(TGF)-β1 was used to induce EMT in A549 cells.Western blotting,immunofluorescence,wound healing assay,and transwell-matrigel invasion chambers were used to identify phenotype changes.Western blotting was also used to observe changes of the expression of eIF5A-2.We down-regulated the eIF5A-2 expression using an eIF5A-2 siRNA and identified the phenotype changes by western blotting and immunofluorescence.We tested the change of migration and invasion capabilities of A549 cells by the wound healing assay and transwell-matrigel invasion chambers.Results:After stimulating with TGF-β1,almost all A549 cells changed to the mesenchymal phenotype and acquired more migration and invasion capabilities.These cells also had higher eIF5A-2 protein expression.Down-regulation of eIF5A-2 expression with eIF5A-2 siRNA transfection could change the cells from mesenchymal to epithelial phenotype and decrease tumor cell migration and invasive capabilities significantly.Conclusions:The expression of eIF5A-2 was up-regulated following EMT phenotype changes in A549 cells,which correlated with enhanced tumor invasion and metastatic capabilities.Furthermore,in the A549 cell line,the process of EMT phenotype change could be reversed by eIF5A-2 siRNA,with a consequent weakening of both invasive and metastatic capabilities.展开更多
Epithelial-mesenchymal transition (EMT) is a highly conserved process that has been well characterised in embryogenesis. Studies have shown that the aberrant activation of EMT in adult epithelia can promote tumour met...Epithelial-mesenchymal transition (EMT) is a highly conserved process that has been well characterised in embryogenesis. Studies have shown that the aberrant activation of EMT in adult epithelia can promote tumour metastasis by repressing cell adhesion molecules,including epithelial (E)-cadherin. Reduced intracellular adhesion may allow tumour cells to disseminate and spread throughout the body. A number of transcription proteins of the Snail superfamily have been implicated in EMT. These proteins have been shown to be over-expressed in advanced gastrointestinal (GI) tumours including oesophageal adenocarcinomas,colorectal carcinomas,gastric and pancreatic cancers,with a concomitant reduction in the expression of E-cadherin. Regulators of EMT may provide novel clinical targets to detect GI cancers early,so that cancers previously associated with a poor prognosis such as pancreatic cancer can be diagnosed before they become inoperable. Furthermore,pharmacological therapies designed to inhibit these proteins will aim to prevent local and distant tumour invasion.展开更多
Gastric cancer is one of the most common malignant tumors worldwide.Due to its intricate initiation and progression mechanisms,early detection and effective treatment of gastric cancer are difficult to achieve.The epi...Gastric cancer is one of the most common malignant tumors worldwide.Due to its intricate initiation and progression mechanisms,early detection and effective treatment of gastric cancer are difficult to achieve.The epithelial-mesenchymal transition(EMT)is characterized as a fundamental process that is critical for embryonic development,wound healing and fibrotic disease.Recent evidence has established that aberrant EMT activation in the human stomach is closely associated with gastric carcinogenesis and tumor progression.EMT activation endows gastric epithelial cells with increased characteristics of mesenchymal cells and reduces their epithelial features.Moreover,mesenchymal cells tend to dedifferentiate and acquire stem cell or tumorigenic phenotypes such as invasion,metastasis and apoptosis resistance as well as drug resistance during EMT progression.There are a number of molecules that indicate the stage of EMT(e.g.,E-cadherin,an epithelial cell biomarker);therefore,certain transcriptional proteins,especially E-cadherin transcriptional repressors,may participate in the regulation of EMT.In addition,EMT regulation may be associated with certain epigenetic mechanisms.The aforementioned molecules can be used as early diagnostic markers for gastric cancer,and EMT regulation can provide potential targets for gastric cancer therapy.Here,we review the role of these aspects of EMT in gastric cancer initiation and development.展开更多
Epithelial-to-mesenchymal transition(EMT) is defined as the transformation of an epithelial cell into a spindle cell with the loss of membrane E-cadherin expression and the gain of mesenchymal markers positivity. In t...Epithelial-to-mesenchymal transition(EMT) is defined as the transformation of an epithelial cell into a spindle cell with the loss of membrane E-cadherin expression and the gain of mesenchymal markers positivity. In the field of colorectal cancer(CRC), first data about EMT was published in 1995 and more than 400 papers had been written up to March 2016. Most of them are focused on the molecular pathways and experimentally-proved chemoresistance. In the present article, an update in the field of EMT in CRC based on the review of the literature and personal experience of the authors is presented. The information about the molecular and immunohistochemical(IHC) particularities of these processes and their possible role in the prognosis of CRC were also up-dated. This article focuses on the IHC quantification of the EMT, the immunoprofile of tumor buds and on the relation between EMT, angiogenesis, and stem cells activation. The EMT-induced chemoresistance vs chemotherapyor radiotherapy-induced EMT and cellular senescence was also synthesized for both conventional and targeted therapy. As a future perspective, the EMTangiogenesis-stemness link could be used as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management of patients with CRC. Association of dexamethasone and angiotensin converting enzyme inhibitors combined with conventional chemotherapies could have clinical benefits in patients with CRC. The main conclusion is that, although many studies have been published, the EMT features are still incompletely elucidated and newly discovered EMT markers provide confusing data in understanding this complicated process, which might have significant clinical impact.展开更多
Liver injuries are repaired by fibrosis and regeneration.The cause of fibrosis and diminished regeneration,especially in liver cirrhosis,is still unknown.Epithelialmesenchymal transition(EMT) has been found to be asso...Liver injuries are repaired by fibrosis and regeneration.The cause of fibrosis and diminished regeneration,especially in liver cirrhosis,is still unknown.Epithelialmesenchymal transition(EMT) has been found to be associated with liver fibrosis.The possibility that EMT could contribute to hepatic fibrogenesis reinforced the concept that activated hepatic stellate cells are not the only key players in the hepatic fibrogenic process and that other cell types,either hepatic or bone marrow-derived cells could contribute to this process.Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis,more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders.The debate on the authenticity of EMT or on its contribution to the fibrogenic process has become very animated.The overall result is a general confusion on the meaning and on the definition of several key aspects.The aim of this article is to describe how EMT participates to hepatic fibrosis and discuss the evidence of supporting this possibility in order to reach reasonable and useful conclusions.展开更多
Hepatocellular carcinoma(HCC)is one of the most prevalent malignant cancers worldwide.Epithelialmesenchymal transition(EMT),which endows epithelial cells with mesenchymal properties,plays an important role in the earl...Hepatocellular carcinoma(HCC)is one of the most prevalent malignant cancers worldwide.Epithelialmesenchymal transition(EMT),which endows epithelial cells with mesenchymal properties,plays an important role in the early stages of metastasis.Conventional cancer therapies have promising effects,but issues remain,such as high rates of metastasis and drug resistance.Thus,exploring and evaluating new therapies is an urgent need.Traditional Chinese medicines(TCMs)have been acknowledged for their multi-target and coordinated intervention effects against HCC.Accumulating evidence indicates that TCM can inhibit the malignancy of cells and the progression of EMT in HCC.However,studies on the effects of TCM on EMT in HCC are scarce.In this review,we summarized recent developments in anti-EMT TCMs and formulae,focusing on their underlying pharmacological mechanisms,to provide a foundation for further research on the exact mechanisms through which TCM affects EMT in HCC.展开更多
文摘AIM:To investigate whether vaccinia-related kinase 1(VRK1)mediates transforming growth factor-beta2(TGF-β2)-caused epithelial-mesenchymal transition(EMT)and inflammatory responses in retinal pigment epithelial(RPE)cells through regulating snail family transcriptional repressor 1(SNAI1),and to validate its role in a proliferative vitreoretinopathy(PVR)mouse model.METHODS:Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model.Western blot detected VRK1 level.The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence,ELISA,Transwell,and scratch assay,and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation.A PVR mouse model was constructed,and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining.Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot.RESULTS:VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment.Overexpression of VRK1 increased cell viability,promoted cell migration and EMT,and the levels of inflammatory factors.Silencing of VRK1 reversed the above indexes.There was a direct interaction between VRK1 and SNAI1,and overexpresssion SNAI1 weakened the impacts of silencing of VRK1.In PVR mice,silencing of VRK1 ameliorated retinal structural damage,decreased proinflammatory factor levels,and suppressed SNAI1 and mesenchymal marker expression.SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses.CONCLUSION:VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells.
基金supported by the National Natural Science Foundation of China(Nos.22206207,22127810,and 22276224)the Natural Science Foundation of Guangdong Province(Nos.2021A1515011546 and 2023A1515010085)the Science and Technology Planning Project of Guangzhou(No.202102080005)。
文摘Epithelial-mesenchymal transition(EMT)plays an irreplaceable role in the development of silicosis.However,molecular mechanisms of EMT induced by silica exposure still remain to be addressed.Herein,metabolic profiles of human alveolar type II epithelial cells(A549 cells)exposed directly to silica were characterized using non-targeted metabolomic approaches.A total of 84 differential metabolites(DMs)were identified in silica-treated A549 cells undergoing EMT,which were mainly enriched in metabolisms of amino acids(e.g.,glutamate,alanine,aspartate),purine metabolism,glycolysis,etc.The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica.Remarkably,glutamine catabolism was significantly promoted in the silica-treated A549 cells,and the levels of related metabolites(e.g.,succinate)and enzymes(e.g.,α-ketoglutarate(α-KG)dehydrogenase)were substantially up-regulated,with a preference toα-KG pathway.Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail(zinc finger transcription factor).Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.
基金Supported by the Fundamental Research Program of Shanxi Province,No.202203021222418Research Program of Shanxi Provincial Health Commission,No.2023061+2 种基金Fundamental Research Cooperation Program of Beijing-Tianjin-Hebei Region of Natural Science Foundation of Tianjin,No.22JCZXJC00140Tianjin Major Science and Technology Project,No.21ZXJBSY00110Tianjin Health and Science and Technology Project,No.TJWJ2024ZK001.
文摘BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.
基金funded by Outstanding Leaders Training Programof Pudong Health Commission of Shanghai(No.PWR12023-03)In-house Project of Shanghai Pudong NewArea People’sHospital(No.E24-02).
文摘Background:Colorectal cancer(CRC)is common and deadly,often leading to metastasis,challenging treatment,and poor outcomes.Understanding its molecular basis is crucial for developing effective therapies.Aims:This study aimed to investigate the role of Myosin Heavy Chain 11(MYH11)in CRC progression,especially its effects on epithelial-mesenchymal transition(EMT)and cell behavior,and to explore its potential regulation by the EMT transcription factor zinc finger E-box binding homeobox 1(ZEB1).Methods:Differential expression analysis was performed in the GSE123390 and TCGA-READ datasets,and 317 intersection genes were identified.The hub gene MYH11 was identified based on Protein-protein interaction(PPI)analysis and expression validation.The effects of MYH11 and the EMT transcription factor(ZEB1)on the behavior of CRC cells were investigated in vitro.Results:Bioinformatics research revealed that MYH11 was considerably downregulated in CRC samples as compared to normal samples.Overexpression of MYH11 inhibited the proliferation,migration,and invasion of CRC cells.Western blotting(WB)testing showed that MYH11 overexpression inhibited EMT by elevating E-cadherin levels while suppressing ZEB1,vimentin,and N-cadherin expressions.By contrast,overexpression of ZEB1 promoted EMT and enhanced migration,invasion,and proliferation of CRC cells.The negative impacts of MYH11 affecting EMT markers and cell behaviors were partially mitigated by co-overexpression of MYH11 and ZEB1,indicating that MYH11 regulates EMT and CRC progression through ZEB1.Conclusion:Our study shows MYH11 curbs CRC growth by blocking EMT and invasion,but ZEB1 overexpression reduces this effect.It uncovers key CRC pathways and suggests MYH11’s therapeutic potential.
基金supported by the Hunan Province Natural Science Foundation Medical Industry Joint Fund(No.2024JJ9421)Clinical Medical Technology Innovation Guide Project of Hunan Province(No.2021SK51418).
文摘Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic nephropathy(DN).Rhein is the main active anthraquinone derivative in several common traditional herbal medicines.This study aimed to investigate the protective effects of Rhein on podocyte ferroptosis and EMT.Methods:The mouse glomerular podocyte cell line MPC5 was stimulated with high glucose(HG),Rhein,and the ferroptosis inhibitor ferrostatin-1(Fer-1).Mechanistic investigations employed plasmids to overexpress and knockdown Sirtuin-1(SIRT1),solute carrier family 7 member 11(SLC7A11),or p53 and measure ferroptosis-or EMT-related indicators.Results:In the HG-injured podocytes,Rhein enhanced cell viability,reduced malondialdehyde(MDA),ferrous iron(Fe2+),and reactive oxygen species(ROS)levels,increased glutathione(GSH)production,accompanied by the restoration of ferroptosis-and EMT-associated indicator expressions.Mechanistically,Rhein induced SIRT1 and SLC7A11 expression and attenuated p53 expression.SIRT1 knockdown upregulated p53 and downregulated SLC7A11,thereby abolishing the protective effects of Rhein against podocyte ferroptosis and EMT.However,the effects of SIRT1 overexpression were reversed by SLC7A11 knockdown.Conclusion:Rhein activated the SIRT1/p53/SLC7A11 axis to protect podocytes against ferroptosis and EMT.This suggests that Rhein has a potential therapeutic effect on DN patients associated with podocyte injury,and targeting SIRT1/p53/SLC7A11 may represent an innovative therapeutic strategy for DN patients.
基金Supported by the Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project on Applied Basic Research,No.202401AY070001-132the Yunnan Provincial Science Foundation,No.2018FE001(-287)+1 种基金National Natural Science Foundation of China,No.81460443the Ten Thousand People Plan of Yunnan Province,No.KH-SWR-MY-2020-002.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a difficult cancer to manage due to its highly invasive and metastatic nature.AIM To investigate the molecular function of transmembrane channel-like 5(TMC5)in vitro and in vivo,with the objective of identifying novel diagnosis and treatment targets for HCC.METHODS The expression of TMC in cancer and normal tissues,along with its correlation with HCC prognosis,was analyzed using the GENT2,GEPIA database,and Human Protein Atlas.COX analysis was conducted to assess the relationship between TMC5 expression and overall survival in TCGA-LIHC patients.Further experiments were conducted to investigate the effect of TMC5 in cancer progression through loss-and gain-of-function assays in vitro and in vivo.RESULTS Bioinformatics revealed that TMC5 expression was generally higher in tumors than in normal tissues,and its expression was associated with poorer patient survival outcomes.TMC5 expression in HCC tissues and cells was consistent with the results of the bioinformatics analysis.Suppression of TMC5 expression reduced migration,invasion,and proliferation,while also decreasing the expression of epithelial-mesenchymal transition(EMT)-associated molecules in MHCC97-LM3 cells.Conversely,higher TMC5 expression significantly increased cell migration,invasion,proliferation,and EMT in MHCC97 L cells.TMC5 knockdown significantly decreased both the formation and spread of nodules in liver tissue,whereas TMC5 overexpression promoted them.CONCLUSION Our study provides compelling evidence that TMC5 is highly expressed in HCC and drives cancer progression through the activation of EMT-mediated invasion.TMC5 could represent a valuable molecular target for the diagnosis and treatment of HCC.
基金Supported by the National Key R&D Program of China,No.2022YFC2503700 and No.2022YFC2503703the National Health Commission Key Laboratory of Nuclear Technology Medical Transformation(Mianyang Central Hospital),No.2023HYX005.
文摘BACKGROUND Esophageal cancer(ESCA)poses a significant challenge in oncology because of the limited treatment options and poor prognosis.Therefore,enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.AIM To define the role of the transcription factor Snail family transcriptional repressor 1(SNAI1)in ESCA,particularly its regulation of radiosensitivity.METHODS A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA.Survival curves correlated SNAI1 levels with radiotherapy outcomes.Colony formation assays,flow cytometry,and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis.Western blot validated protein expression,while Chromatin im-munoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition(EMT).RESULTS SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease.Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy.Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation(IR),resulting in remarkable tumor regression upon IR treatment in vivo.This study underscores the direct involvement of SNAI1 in the regulation of EMT,particularly under IR-induced conditions.Furthermore,inhibiting deacetylation effectively suppresses EMT,suggesting a potential avenue to enhance the response to radiotherapy in ESCA.CONCLUSION This study highlights SNAI1's role in ESCA radiosensitivity,offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.
基金supported by grants from the Key Scientific and Technological Projects of Ningbo(No.2021Z133)Ningbo Top Medical and Health Research Program(No.2023020612)+2 种基金National Natural Science Foundation of China(No.81702367)the Medical and Health Research Project of Zhejiang Province(No.2024KY319)the Youth Medical Backbone Talents Training Program of Ningbo.
文摘Circular RNAs(circRNAs)are formed by splicing of precursor RNAs and covalently linked at the 5′and 3′ends.Dysregulated circRNAs are closely related to the epithelial-mesenchymal transition(EMT)of gastrointestinal malignancies.CircRNAs,including circRNA_0008717,circGOT1,circ-DOCK5,circVPS33B,circPVT1,circMET,circ-OXCT1,circ_67835,circRTN4,circ_0087502,circFNDC38,circ_PTEN1,circPGPEP1,and circ-E-Cad are involved in the EMT process of gastrointestinal malignancies through a variety of mechanisms,such as regulating EMT-inducing transcription factors,signaling pathways,and tumor microenvironments.Gastrointestinal(GI)malignancies are common malignant tumors worldwide,and the heterogeneity and easy metastasis of gastrointestinal malignancies limit the effectiveness of medical treatments.Therefore,investigating the molecular mechanisms involved in the pathogenesis of gastrointestinal malignancies is essential for clinical treatment.This article summarizes the biological roles and molecular mechanism of circRNAs in EMT of gastrointestinal malignancies,providing a theoretical basis for applying EMT-related circRNAs in targeted therapy.
基金Supported by the Henan Province Science and Technology Development Plan,No.242102311124Key Medical Scientific and Technological Project of Henan Province,No.SBGJ202102188+1 种基金Henan Provincial Medical Science and Technology Project,No.LHGJ20221012Fundamental Research Funds for the Universities of Henan Province,No.NSFRF240308.
文摘BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.
基金Ministry of Education Industry-University Co-operation Collaborative Education Project,No.202102242020.
文摘BACKGROUND Activation of the epithelial-mesenchymal transition(EMT),a pivotal process in tumor metastasis and evasion,as well as the NLRP3 inflammasome,both promote colorectal cancer(CRC)progression.Recent studies have shown that Transmembrane protein 176B(TMEM176B)regulates NLRP3 and promotes CRC malignant phenotypes.AIM To investigate the role of TMEM176B in modulating NLRP3 inflammasome and its implications on EMT and tumor progression in CRC.METHODS CRC in situ mouse and co-cultured cell models were established using CT26 cells,BALB/c mice,and primary cultured mouse natural killer(NK)cells.Short hairpin RNA knocked down TMEM176B and NLRP3 expression in CT26 cells.Fluorescence imaging,Terminal deoxynucleotidyl transferase dUTP nick end labeling assays,immunohistochemistry staining,flow cytometry,and molecular assays were used to investigate the effects of TMEM176B knockdown on the NLRP3 inflammasome in NK cells to assess tumor metastasis,apoptosis,and EMT indicators.RESULTS Silencing TMEM176B in CRC mice significantly reduced tumor metastasis,proliferation,and EMT,while activating apoptosis,NLRP3 inflammasome,and NK cell activity.Furthermore,silencing TMEM176B in co-cultured cell models inhibited cell migration and invasion,and promoted apoptosis.The interference of NLRP3 reversed these effects by modulating key proteins such as phosphorylated nuclear factor kappa B subunit 1 p65,matrix metallopeptidase 9,and transforming growth factor-β.CONCLUSION This study highlights the critical role of TMEM176B/NLRP3 in CRC progression and provides a basis for targeting this axis as a novel therapeutic approach to manage CRC progression and metastasis.
文摘Chen et al demonstrated that regulator of G protein signaling(RGS)4 promotes gastric cancer(GC)progression by activating the focal adhesion kinase/phospha-tidyl-inositol-3-kinase/protein kinase B pathway and inducing epithelial-mesen-chymal transition.Although their multilevel approach integrating clinical data,functional assays,and xenograft models demonstrated a key role for RGS4 in GC pathogenesis,several limitations should be considered.The mechanism of the RGS4-focal adhesion kinase interaction remains unclear,specifically whether it involves direct binding or intermediaries.The clinical analysis of 90 patients lacks stratification by GC subtypes or immune features,potentially limiting generaliz-ability.Furthermore,fully validating RGS4’s oncogenic role requires additional studies,including functional assays in chemotherapy-resistant and metastatic cell lines,metastasis models including orthotopic implantation and tail vein injection,and comparison with other RGS family members.Addressing these via targeted mechanistic studies and expanded clinical validation could strengthen RGS4’s po-tential as a therapeutic target in GC.
基金Supported by the National Natural Science Foundation of China,No.82372646Research Fund of Anhui Institute of Translational Medicine,No.2023zhyx-C70 and No.2023zhyx-C80.
文摘BACKGROUND Helicobacter pylori(H.pylori)infection is widely considered to be a major risk factor for gastric cancer,contributing to its development through the Correa cascade.Yin Yang 1(YY1)is a transcription factor that acts as a promoter or suppressor of cancer progression.However,the role of YY1 in the inflammatory transformation associated with H.pylori-induced gastric cancer remains unclear.AIM To explore the expression of YY1 in gastric cancer and its impact on cancer progression with H.pylori infection.METHODS H.pylori bacteria were cocultured with GSE1 cells,AGS cells,and SGC7901 cells,as well as in infected and xenograft mouse models.Expression of YY1,members of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway,and epithelial-mesenchymal transition(EMT)-related proteins in gastric cancer was examined using Western blotting,quantitative realtime polymerase chain reaction,and immunohistochemistry.Survival analysis was performed using the Kaplan-Meier method with the log-rank test.The role of YY1 in gastric cancer cell proliferation was further evaluated through in vitro and in vivo assays.RESULTS YY1 was highly expressed in gastric cancer tissues and cells.Kaplan-Meier survival curves indicated that high YY1 expression correlated with a poor prognosis.YY1 expression showed a gradually increasing trend in H.pyloriinduced gastritis and gastric tumors.In vivo and in vitro experiments demonstrated that H.pylori infection promoted phosphorylation of JAK2 and STAT3,thereby activating the EMT pathway,in which YY1 played a key role.YY1 and JAK2 interaction was validated by chromatin immunoprecipitation.YY1 knockdown or pharmacological inhibition reversed EMT and suppressed gastric cancer cell proliferation and metastasis.CONCLUSION These results suggest that YY1 plays an important role in progression of H.pylori-induced gastric cancer by activating EMT.
基金Supported by grants from the Natural Science Foundation of China (No.81000998)New Teachers Foundation of Ministry of Education of China (No. 20090141120003)
文摘Objective: Epithelial-mesenchymal transition (EMT) is a critical early event for the invasion and metastasis of many carcinomas. In the present study, we examined EMT markers in the residual cancer cells of hepatocellular carcinoma (HCC) after radiotherapy. Methods: Eight patients with large HCC who underwent hepatectomy with preoperative radiothera- py were studied. The expressions of E-cadherin and vimentin were determined immunohistochemically in the residual cancer cells of HCC following radiotherapy, and also in the pre-radiotherapy biopsy cancer cells. Results: Histological analysis showed that some residual cancer cells of HCC displayed an elongated spindle or fibroblast-like shape. The expression of E- cadherin was markedly reduced or negative in the spindle residual cancer cells, but the expression of vimentin significantly in- duced. However, the above changes were not found in the pre-radiotherapy biopsy cancer cells. Conclusion: EMT is induced in the residual cancer cells of HCC following radiotherapy, which may facilitate the systemic dissemination of cancer cells.
文摘Objective:To study the correlation of Claudins6 (CLDN6) gene expression in meningioma tissue with the expression of matrix metalloproteinases (MMPs)/tissue inhibitors of matrix metalloproteinase (TIMPs) and epithelial-mesenchymal transition (EMT) genes.Methods:Meningioma tissue samples that were surgically removed in Yibin First People's Hospital between April 2014 and May 2017 were selected, normal arachnoid tissue samples that were collected from decompressive craniectomy in Yibin First People's Hospital during the same period were selected, and the expression of CLDN6, MMPs/TIMPs and EMT genes in tissues were determined.Results: CLDN6 protein expression in meningioma tissue was significantly lower than that in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue were significantly higher than those in normal arachnoid tissue while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly lower than those in normal arachnoid tissue;EMMPRIN, MMP2, MMP9, Vimentin and N-cadherin protein expression in meningioma tissue with higher CLDN6 expression were significantly lower than those in meningioma tissue with lower CLDN6 expression while TIMP1, TIMP2, E-cadherin andα-catenin protein expression were significantly higher than those in meningioma tissue with lower CLDN6 expression. Conclusion: Lowly expressed CLDN6 gene in meningioma tissue can increase the hydrolysis activity of MMPs, induce epithelial-mesenchymal transition and thus promote the invasive growth of meningioma.
基金Project supported by the Natural Science Fundation of Ningbo (No. 2011A610052)the Zhejiang Provincial Natural Science Fundation (No. LY12H16002) of China
文摘Background:Epithelial-mesenchymal transition(EMT) is believed to be the critical process in malignant tumor invasion and metastases,and has a great influence on improving the survival rate in non-small-cell lung cancer(NSCLC) patients.Recent studies suggested that eukaryotic initiation factor 5A-2(eIF5A-2) might serve as an adverse prognostic marker of survival.We detected eIF5A-2 in NSCLC A549 cells,and found that the invasive capability correlates with the eIF5A-2 expression.Methods:Transforming growth factor(TGF)-β1 was used to induce EMT in A549 cells.Western blotting,immunofluorescence,wound healing assay,and transwell-matrigel invasion chambers were used to identify phenotype changes.Western blotting was also used to observe changes of the expression of eIF5A-2.We down-regulated the eIF5A-2 expression using an eIF5A-2 siRNA and identified the phenotype changes by western blotting and immunofluorescence.We tested the change of migration and invasion capabilities of A549 cells by the wound healing assay and transwell-matrigel invasion chambers.Results:After stimulating with TGF-β1,almost all A549 cells changed to the mesenchymal phenotype and acquired more migration and invasion capabilities.These cells also had higher eIF5A-2 protein expression.Down-regulation of eIF5A-2 expression with eIF5A-2 siRNA transfection could change the cells from mesenchymal to epithelial phenotype and decrease tumor cell migration and invasive capabilities significantly.Conclusions:The expression of eIF5A-2 was up-regulated following EMT phenotype changes in A549 cells,which correlated with enhanced tumor invasion and metastatic capabilities.Furthermore,in the A549 cell line,the process of EMT phenotype change could be reversed by eIF5A-2 siRNA,with a consequent weakening of both invasive and metastatic capabilities.
文摘Epithelial-mesenchymal transition (EMT) is a highly conserved process that has been well characterised in embryogenesis. Studies have shown that the aberrant activation of EMT in adult epithelia can promote tumour metastasis by repressing cell adhesion molecules,including epithelial (E)-cadherin. Reduced intracellular adhesion may allow tumour cells to disseminate and spread throughout the body. A number of transcription proteins of the Snail superfamily have been implicated in EMT. These proteins have been shown to be over-expressed in advanced gastrointestinal (GI) tumours including oesophageal adenocarcinomas,colorectal carcinomas,gastric and pancreatic cancers,with a concomitant reduction in the expression of E-cadherin. Regulators of EMT may provide novel clinical targets to detect GI cancers early,so that cancers previously associated with a poor prognosis such as pancreatic cancer can be diagnosed before they become inoperable. Furthermore,pharmacological therapies designed to inhibit these proteins will aim to prevent local and distant tumour invasion.
基金Supported by National Natural Science Foundation of China,No.81172186
文摘Gastric cancer is one of the most common malignant tumors worldwide.Due to its intricate initiation and progression mechanisms,early detection and effective treatment of gastric cancer are difficult to achieve.The epithelial-mesenchymal transition(EMT)is characterized as a fundamental process that is critical for embryonic development,wound healing and fibrotic disease.Recent evidence has established that aberrant EMT activation in the human stomach is closely associated with gastric carcinogenesis and tumor progression.EMT activation endows gastric epithelial cells with increased characteristics of mesenchymal cells and reduces their epithelial features.Moreover,mesenchymal cells tend to dedifferentiate and acquire stem cell or tumorigenic phenotypes such as invasion,metastasis and apoptosis resistance as well as drug resistance during EMT progression.There are a number of molecules that indicate the stage of EMT(e.g.,E-cadherin,an epithelial cell biomarker);therefore,certain transcriptional proteins,especially E-cadherin transcriptional repressors,may participate in the regulation of EMT.In addition,EMT regulation may be associated with certain epigenetic mechanisms.The aforementioned molecules can be used as early diagnostic markers for gastric cancer,and EMT regulation can provide potential targets for gastric cancer therapy.Here,we review the role of these aspects of EMT in gastric cancer initiation and development.
基金Supported by University of Medicine and Pharmacy of TirguMures,Romania,Team Research Projects Frame:UMFTGMPO-CC-02-F01,No.19/2014
文摘Epithelial-to-mesenchymal transition(EMT) is defined as the transformation of an epithelial cell into a spindle cell with the loss of membrane E-cadherin expression and the gain of mesenchymal markers positivity. In the field of colorectal cancer(CRC), first data about EMT was published in 1995 and more than 400 papers had been written up to March 2016. Most of them are focused on the molecular pathways and experimentally-proved chemoresistance. In the present article, an update in the field of EMT in CRC based on the review of the literature and personal experience of the authors is presented. The information about the molecular and immunohistochemical(IHC) particularities of these processes and their possible role in the prognosis of CRC were also up-dated. This article focuses on the IHC quantification of the EMT, the immunoprofile of tumor buds and on the relation between EMT, angiogenesis, and stem cells activation. The EMT-induced chemoresistance vs chemotherapyor radiotherapy-induced EMT and cellular senescence was also synthesized for both conventional and targeted therapy. As a future perspective, the EMTangiogenesis-stemness link could be used as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management of patients with CRC. Association of dexamethasone and angiotensin converting enzyme inhibitors combined with conventional chemotherapies could have clinical benefits in patients with CRC. The main conclusion is that, although many studies have been published, the EMT features are still incompletely elucidated and newly discovered EMT markers provide confusing data in understanding this complicated process, which might have significant clinical impact.
基金Supported by The National Research Foundation of Korea Grant funded by the Korean Government,No.2012R1A1A401015639
文摘Liver injuries are repaired by fibrosis and regeneration.The cause of fibrosis and diminished regeneration,especially in liver cirrhosis,is still unknown.Epithelialmesenchymal transition(EMT) has been found to be associated with liver fibrosis.The possibility that EMT could contribute to hepatic fibrogenesis reinforced the concept that activated hepatic stellate cells are not the only key players in the hepatic fibrogenic process and that other cell types,either hepatic or bone marrow-derived cells could contribute to this process.Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis,more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders.The debate on the authenticity of EMT or on its contribution to the fibrogenic process has become very animated.The overall result is a general confusion on the meaning and on the definition of several key aspects.The aim of this article is to describe how EMT participates to hepatic fibrosis and discuss the evidence of supporting this possibility in order to reach reasonable and useful conclusions.
基金supported by Natural Science Foundation of Shanghai Minhang District(No.2019MHZ062)Shanghai Key Specialty Construction Project of Clinical Pharmacy(Minhang District,No.2018YXZDZK)+1 种基金National Natural Science Foundation of China(No.81700065)the Talent Development Special Funds(leading talent)project of Shanghai Minhang District。
文摘Hepatocellular carcinoma(HCC)is one of the most prevalent malignant cancers worldwide.Epithelialmesenchymal transition(EMT),which endows epithelial cells with mesenchymal properties,plays an important role in the early stages of metastasis.Conventional cancer therapies have promising effects,but issues remain,such as high rates of metastasis and drug resistance.Thus,exploring and evaluating new therapies is an urgent need.Traditional Chinese medicines(TCMs)have been acknowledged for their multi-target and coordinated intervention effects against HCC.Accumulating evidence indicates that TCM can inhibit the malignancy of cells and the progression of EMT in HCC.However,studies on the effects of TCM on EMT in HCC are scarce.In this review,we summarized recent developments in anti-EMT TCMs and formulae,focusing on their underlying pharmacological mechanisms,to provide a foundation for further research on the exact mechanisms through which TCM affects EMT in HCC.
