AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identifi...AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule(EpCAM)(E-CTC), the mesenchymal cell markers vimentin and twist(M-CTC), or both(E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio(NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage(P < 0.01) and distant metastasis(P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation(P < 0.01).CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.展开更多
Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenviro...Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition(EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.展开更多
BACKGROUND As one of the most common tumors,gastric cancer(GC)has a high mortality rate,since current examination approaches cannot achieve early diagnosis.Fusobacterium nucleatum(Fn)primarily colonized in the oral ca...BACKGROUND As one of the most common tumors,gastric cancer(GC)has a high mortality rate,since current examination approaches cannot achieve early diagnosis.Fusobacterium nucleatum(Fn)primarily colonized in the oral cavity,has been reported to be involved in the development of gastrointestinal tumor.Until now,little is known about the relationship between salivary Fn and GC.AIM To determine whether salivary Fn could be a biomarker to diagnose GC and explore the influence of Fn on GC cells.METHODS The abundance of Fn in saliva was quantified by droplet digital polymerase chain reaction in 120 GC patients,31 atrophic gastritis(AG)patients,35 non-AG(NAG)patients,26 gastric polyp(GP)patients,and 20 normal controls(NC)from Qilu Hospital of Shandong University from January 2019 to December 2020.Receiver operating characteristic(ROC)curve analysis was performed to evaluate the diagnostic value of Fn as well as traditional serum tumor markers,including carcinoembryonic antigen(CEA),carbohydrate antigen(CA)19-9,and CA72-4.Transwell assay and wound-healing assay were conducted to assess the influence of Fn infection on GC cells.The expression of epithelial-mesenchymal transition(EMT)markers was detected using western blot assay.RESULTS We found that the level of salivary Fn in GC patients was significantly increased compared with those in AG,NAG,and GP patients and NC(P<0.001).ROC curve analysis showed a favorable capability of Fn(73.33% sensitivity;82.14%specificity;area under the curve:0.813)in GC diagnosis,which was superior to that of CEA,CA19-9,CA72-4,ferritin,and sialic acid.The Fn level in saliva of GC patients was increased as the TNM stage increased.GC patients with lymph node metastasis had higher Fn levels than those without metastasis.Both transwell and wound-healing assays indicated that Fn infection promoted the migration and invasion of GC cells.Western blot analysis showed that Fn infection decreased the expression of E-cadherin and increased the expressions of N-cadherin,vimentin,and snail.CONCLUSION Fn abundance in saliva could be used as a promising biomarker to diagnose GC,and Fn infection could promote GC metastasis by accelerating the EMT process.展开更多
The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tum...The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.展开更多
BACKGROUND Tumor budding,is a promising prognostic hallmark in many cancers,and can help us better assess the degree of malignancy in gastric cancer(GC)and in colorectal cancer.In the past few years,several articles o...BACKGROUND Tumor budding,is a promising prognostic hallmark in many cancers,and can help us better assess the degree of malignancy in gastric cancer(GC)and in colorectal cancer.In the past few years,several articles on the relationship between tumor budding and GC have been published,but different results have been observed.As the relationship between tumor budding and GC remains controversial,we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis.AIM To systematically evaluate the prognostic and pathological impact of tumor budding in GC.METHODS Literature searches were conducted in the PubMed,Cochrane Library,EMBASE and Web of Science databases,and 7 cohort studies involving 2178 patients met our criteria and included in the analysis.The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding,and the cut-off values for tumor budding varied across the included studies.The hazard ratios(HRs)with 95%confidence intervals(CIs)were calculated to estimate the impact of tumor budding on overall survival(OS)in GC patients.The odds ratios(ORs)with 95%CIs were used to determine the correlation between tumor budding and pathological parameters(tumor stage,tumor differentiation,lymphovascular invasion,lymph node metastasis)of GC.RESULTS Seven studies involving 2178 patients were included in the meta-analysis.The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage(OR=6.63,95%CI:4.01-10.98,P<0.01),tumor differentiation(OR=3.74,95%CI:2.68-5.22,P<0.01),lymphovascular invasion(OR=7.85,95%CI:5.04-12.21,P<0.01),and lymph node metastasis(OR=5.75,95%CI:3.20-10.32,P<0.01).Moreover,high-grade tumor budding predicted a poor 5-year OS(HR=1.79,95%CI:1.53-2.05,P<0.01)in patients with GC and an adverse 5-year OS(HR=1.93,95%CI:1.45-2.42,P<0.01)in patients with intestinal-type GC.CONCLUSION High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.展开更多
Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investi...Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to PD.Methods:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6J mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF.HE and Masson staining were performed to evaluate the extent of PF.The therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,Western blotting,and peritoneal function analyses.Epithelial-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%PDF.Cells were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Cell Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells.Results:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs.The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD mice.We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice.Compared with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response,with markedly increased peritoneal thickness and higher expression ofα-SMA,collagen-I,fibronectin,and ECM1.The mice with PD showed decreased miR-27a-3p.Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment,while PF and mesothelial damage were significantly ameliorated.Additionally,markers of fibrosis(α-SMA,collagen-I,fibronectin,ECM1)and profibrotic cytokines(TGF-β1,PDGF)were downregulated at the mRNA and protein levels after BMSC-Exos treatment.In HMrSV5 cells,BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF.Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin(epithelial marker)and decreased expression ofα-SMA,Snail,and vimentin(mesenchymal markers)compared to those of the 4.25%PDF-treated cells.Importantly,a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p.TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos.Conclusion:The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.展开更多
BACKGROUND Gastric cancer(GC)is considered as one of the most widespread malignancies.Emerging evidence has shown that lncRNAs can function as important oncogenes or tumor suppressors during GC progression.AIM To inve...BACKGROUND Gastric cancer(GC)is considered as one of the most widespread malignancies.Emerging evidence has shown that lncRNAs can function as important oncogenes or tumor suppressors during GC progression.AIM To investigate the effect and mechanism of lncRNA cancer susceptibility 20(CASC20)in the proliferation and metastasis of GC cells.METHODS Data mining and clinical samples were used to evaluate the expression of CASC20 in GC and adjacent tissues.CASC20 was down-regulated in GC cells by shortinterfering RNA.Cell proliferation was evaluated by CCK-8 assay,and cell migration and invasion were detected by wound healing and Transwell assays.The expressions of proteins related to epithelial-mesenchymal transition were detected by western blot assay.RESULTS The expression of CASC20 was increased in GC tumor tissues and various GC cell lines.High CASC20 expression was correlated with a high risk of lymphatic metastasis and poor prognosis in GC patients.In vitro assays showed that silencing CASC20 reduced cell proliferation,migration,and invasion in GC cells.Mechanistic studies revealed that CASC20 exhibits oncogenic functions by regulating MEMO1 expression through competitive endogenous binding to miR-143-5p,leading to induction of epithelial-mesenchymal transition.CONCLUSION Our findings indicate that CASC20 serves as a tumor promoter by regulating metastasis in GC via the miR-143-5p/MEMO1 axis.CASC20 may be a potential therapeutic target for GC.展开更多
BACKGROUND Esophageal squamous cell carcinoma(ESCC),the predominant type of esophageal cancer,has a 5-year survival rate less than 20%.Although the cause of poor prognosis is the high incidence and mortality of ESCC,t...BACKGROUND Esophageal squamous cell carcinoma(ESCC),the predominant type of esophageal cancer,has a 5-year survival rate less than 20%.Although the cause of poor prognosis is the high incidence and mortality of ESCC,the high rate of metastasis after esophageal cancer surgery is the main cause of death after the surgery.Bromodomain-containing protein 4(BRD4),an epigenetic reader of chromatinacetylated histones in tumorigenesis and development,plays an essential role in regulating oncogene expression.BRD4 inhibition and BRD4 inhibition-based treatment can potentially suppress ESCC growth.However,the effects and mechanisms of action of BRD4 on ESCC cell migration remain unclear.AIM To explore the effect of BRD4 on cell migration of ESCC in vitro and its possible molecular mechanism.METHODS Human ESCC cell lines KYSE-450 and KYSE-150 were used.The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay was performed to examine cell proliferation,and the transwell migration assay was conducted to test ESCC cell migration.JQ1,a BRD4 inhibitor,was applied to cells,and BRD4 siRNA was transfected into ESCC cells to knockdown endogenous BRD4.GFP-RFP-LC3 adenovirus was infected into ESCC cells to evaluate the effect of JQ1 on autophagy.Western blotting was performed to determine the protein levels of BRD4,E-cadherin,vimentin,AMP-activated protein kinase(AMPK),and p-AMPK.RESULTS BRD4 was either downregulated by small interfering RNA or pretreated with JQ1 in ESCC cells,leading to increased tumor migration in ESCC cells in a dose-and time-dependent manner.Inhibition of BRD4 not only significantly suppressed cell proliferation but also strongly increased cell migration by inducing epithelial-mesenchymal transition(EMT).The protein expression of vimentin was increased and E-cadherin decreased in a dose-dependent manner,subsequently promoting autophagy in KYSE-450 and KYSE-150 cells.Pretreatment with JQ1,a BRD4 inhibitor,inhibited BRD4-induced LC3-II activation and upregulated AMPK phosphorylation in a dosedependent manner.Additionally,an increased number of autophagosomes and autolysosomes were observed in JQ1-treated ESCC cells.The autophagy inhibitor 3-methyladenine(3-MA)reversed the effects of BRD4 knockdown on ESCC cell migration and blocked JQ1-induced cell migration.3-MA also downregulated the expression of vimentin and upregulation E-cadherin.CONCLUSION BRD4 inhibition enhances cell migration by inducing EMT and autophagy in ESCC cells via the AMPK-modified pathway.Thus,the facilitating role on ESCC cell migration should be considered for BRD4 inhibitor clinical application to ESCC patients.展开更多
AIM: To evaluate the effects of epidermal growth factor(EGF) on transforming growth factor-beta1(TGF-β1)-induced epithelial-mesenchymal transition(EMT) in human corneal epithelial cells(HCECs). METHODS: HCECs were cu...AIM: To evaluate the effects of epidermal growth factor(EGF) on transforming growth factor-beta1(TGF-β1)-induced epithelial-mesenchymal transition(EMT) in human corneal epithelial cells(HCECs). METHODS: HCECs were cultured and treated with TGF-β1 for establishing the model of EMT in vitro. Biological effect of EGF on TGF-β1-induced EMT was evaluated. Proteins and m RNAs expression changes of E-cadherin, N-cadherin and Fibronectin(EMT-relative markers) after TGF-β1 or TGF-β1 combined EGF treatment were detected by Western blot and RT-PCR, respectively. Viability and migration of HCECs were measured by CCK-8, transwell cell migration assay and cell scratch wound healing assay. Activation of Smad2, ERK, p38, JNK and Akt signaling pathways were evaluated by Western blot. Inhibitors of relevant signaling pathways were added to the HCECs to explore the key signal mechanism.RESULTS: With treatment of TGF-β1 only, three EMTrelative proteins and m RNA expression showed that EMT up-regulated in a concentration-dependent and time-dependent manner, with significantly decreasing cell viability(TGF-β1≥5 ng/m L, P<0.05) and increasing cell migration(TGF-β1≥5 ng/m L, P<0.01). The phosphorylation of Smad2 and p38 was a key process of TGF-β1-induced EMT. Meanwhile, EMT-relative proteins and m RNA expression showed that EGF inhibited TGF-β1-indued EMT, with significantly increasing cell viability(EGF≥10 ng/m L, P<0.01). It was noteworthy that EGF significantly enhanced cell migration although EMT was inhibited(EGF≥10 ng/m L, P<0.01), and the blockage of p38(by SB202190, a p38 inhibitor) was a potential mechanism of this phenomenon. CONCLUSION: EGF inhibits TGF-β1-induced EMT via suppressive p38, and promotes cells proliferation and migration in a non-EMT process by inhibiting p38 pathway.展开更多
Management of unresectable urothelial cancer(UC)has been a clinical challenge for decades.While drug resistance is a key issue,precise understanding of biology of UC metastasis is another challenge for the improvement...Management of unresectable urothelial cancer(UC)has been a clinical challenge for decades.While drug resistance is a key issue,precise understanding of biology of UC metastasis is another challenge for the improvement of treatment outcome of UC patients.Introduction of the cell biology concepts including epithelial-mesenchymal transition(EMT)and cancer stemness seems to explain UC metastasis.Molecular genetics based on gene expression profiling,next generation sequencing,and explosion of non-coding RNA world has opened the door to intrinsic molecular subtyping of UC.Next steps include,based on the recently accumulated understanding,the establishment of novel disease models representing UC metastasis in various experimental platforms,particularly in vivo animal systems.Indeed,novel knowledge molecular genetics has not been fully linked to the modeling of UC metastasis.Further understanding of bladder carcinogenesis is needed particularly with regard to cell of origin related to tumor characteristics including driver gene alterations,pathological differentiations,and metastatic ability.Then we will be able to establish better disease models,which will consequently lead us to further understanding of biology and eventually the development of novel therapeutic strategies for UC metastasis.展开更多
A recent publication highlights the importance of high yes-associated protein(YAP) expressing cells in liver regeneration following partial hepatectomy.Although the names of the cell populations described in these art...A recent publication highlights the importance of high yes-associated protein(YAP) expressing cells in liver regeneration following partial hepatectomy.Although the names of the cell populations described in these articles [hybrid periportal hepatocytes(HybHP) or epithelial-mesenchymal transition(EMT)-reprogrammed hepatocytes] are not identical, they all express high levels of YAP.We hypothesize that the HybHP and EMT-reprogrammed hepatocytes might be a similar cell population. Hippo signaling is the primary pathway that regulates YAP activity. According to the contribution of these two types of cells to liver regeneration and the high YAP expression, Hippo-YAP signaling activation may be a common regulatory pathway experienced by cells undergoing dedifferentiation and reactivating proliferative activity during liver regeneration.Although no evidence has shown that HybHP cells contribute to hepatocellular carcinoma in mouse models, we can not rule out the possibility that these highly regenerative cells can further develop into tumor cells when they acquire mutations caused by viral infection or other risk factors like alcohol. The detailed mechanistic insight of the regulation of YAP expression and activity in HybHP(or other types of cells contributing to liver regeneration) is unknown. We hypothesize that liver regeneration under various conditions will eventually lead to divergent consequences, likely due to the duration of YAP activation regulated by Hippo-large tumor suppressor 1 and 2 pathway in a context-and cell typedependent manner.展开更多
Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"...Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"in the AGS cells wound healing assay was incorrectly inserted during the preparation of the submission;the correct figure is provided in this correction.展开更多
AIM:To evaluate the effect of bone morphogenetic protein-6(BMP-6)on transforming growth factor(TGF)-β_(2)-induced epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE).METHODS:Adult retinal pigment...AIM:To evaluate the effect of bone morphogenetic protein-6(BMP-6)on transforming growth factor(TGF)-β_(2)-induced epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE).METHODS:Adult retinal pigment epithelial cell line(ARPE-19)were randomly divided into control,TGF-β_(2)(5μg/L),and BMP-6 small interfering RNA(siRNA)group.The cell morphology was observed by microscopy,and the cell migration ability were detected by Transwell chamber.The EMT-related indexes and BMP-6 protein levels were detected by Western blotting.Furthermore,a BMP-6 overexpression plasmid was constructed and RPE cells were divided into the control group,TGF-β_(2)+empty plasmid group,BMP-6 overexpression group,and TGF-β_(2)+BMP-6 overexpression group.The EMT-related indexes and extracellular regulated protein kinases(ERK)protein levels were detected.RESULTS:Compared with the control group,the migration of RPE cells in the TGF-β_(2) group was significantly enhanced.TGF-β_(2) increased the protein expression levels ofα-smooth muscle actin(α-SMA),fibronectin and vimentin but significantly decreased the protein levels of E-cadherin and BMP-6(P<0.05)in RPE.Similarly,the migration of RPE cells in the BMP-6 siRNA group was also significantly enhanced.BMP-6 siRNA increased the protein expression levels ofα-SMA,fibronectin and vimentin but significantly decreased the protein expression levels of E-cadherin(P<0.05).Overexpression of BMP-6 inhibited the migration of RPE cells induced by TGF-β_(2) and prevented TGF-β_(2) from affecting EMT-related biomarkers(P<0.05).CONCLUSION:BMP-6 prevents the EMT in RPE cells induced by TGF-β_(2),which may provide a theoretical basis for the prevention and treatment of proliferative vitreoretinopathy.展开更多
Background:Adaptative desaturation in fatty acid(FA)is an emerging hallmark of cancer metabolic plasticity.Desaturases such as stearoyl-CoA desaturase(SCD)and fatty acid desaturase 2(FADS2)have been implicated in mult...Background:Adaptative desaturation in fatty acid(FA)is an emerging hallmark of cancer metabolic plasticity.Desaturases such as stearoyl-CoA desaturase(SCD)and fatty acid desaturase 2(FADS2)have been implicated in multiple cancers,and their dominant and compensatory effects have recently been highlighted.However,how tumors initiate and sustain their self-sufficient FA desaturation to maintain phenotypic transition remains elusive.This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression.Methods:The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts,which guided subsequent functional and mechanistic investigations.The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines.Specific desaturation activities were characterized through various isomer-resolved lipidomics methods and sensitivity assays using desaturase inhibitors.In-situ lipid profilingwas conducted using multiplex stimulated Raman scattering imaging.Functional assays were performed both in vitro and in vivo,with RNA-sequencing employed for the mechanism verification.Results:After integration of the RNA-protein-metabolite levels,the data revealed that a reprogramming fromSCD-dependent to FADS2-dependent desaturation was linked to cancer epithelial-mesenchymal transition(EMT)and progression in both patients and cell lines.FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity.A FADS2/β-catenin selfreinforcing feedback loop facilitated the degree of lipid unsaturation,membrane fluidity,metastatic potential and EMT signaling.Moreover,SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate-activated protein kinase activation.Notably,this desaturation reprogramming increased transforming growth factor-β2,effectively sustaining aggressive phenotypes and metabolic plasticity during EMT.Conclusions:These findings revealed a metabolic reprogramming from SCDdependent to FADS2-dependent desaturation during cancer EMT and progression,which concurrently supports EMT plasticity.Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.展开更多
Extracellular vesicles from highly metastatic tumor cells have been shown to mediate epithelial-mesenchymal transition(EMT)-related events in recipient cells.In endometrial epithelial cells,EMT processes are known to ...Extracellular vesicles from highly metastatic tumor cells have been shown to mediate epithelial-mesenchymal transition(EMT)-related events in recipient cells.In endometrial epithelial cells,EMT processes are known to be involved in the development of adenomyosis.We aimed to investigate whether adenomyosis-derived extracellular vesicles(AMEVs)are able to induce an EMT process in endometrial epithelial cells.In this study,AMEVs were isolated from patients with adenomyosis and characterized by transmission electron microscopy,Western blot,and nanoparticle tracking.Primary endometrial epithelial cells(EECs)were derived from normal endometrium tissues from patients with leiomyoma and co-cultured with AMEVs in vitro.AMEV uptake was examined by fluorescence confocal microscopy.The invasion of EECs was confirmed by Transwell assay.Immunohistochemistry,Western blot,and qRT-PCR were performed on EECs to illustrate the expression levels of cytokeratin 19,E-cadherin,vimentin,and zinc finger E-boxbinding homeobox 1(ZEB1).The results indicated that the cellular fluorescence intensity gradually increased after 48 h of co-culture,but decreased after 72 h.After co-culturing with AMEVs for 72 h,EECs expressed significantly lower levels of cytokeratin 19 and E-cadherin,and significantly higher levels of vimentin and ZEB1.Together these results demonstrated that AMEVs induce an EMT process and enhance the invasion of EECs.These changes may contribute to the pathogenesis and progression of adenomyosis.展开更多
Epithelial-mesenchymal Transition(EMT)is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance,metastasis,and recurrence.This dynamic and revers...Epithelial-mesenchymal Transition(EMT)is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance,metastasis,and recurrence.This dynamic and reversible events is governed by a network of EMT-transcription factors(EMT-TFs)through epigenetic regulation.Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates;this suggests that EMT is subjected to the metabolic regulation.Conversely,EMT rewires metabolic program to accommodate cellular changes during EMT.Here we summarize the latest findings regarding the epigenetic regulation of EMT,and discuss the mutual interactions among metabolism,epigenetic regulation,and EMT.Finally,we provide perspectives of how this interplay contributes to cellular plasticity,which may result in the clinical manifestation of tumor heterogeneity.展开更多
The damage of proximal tubular epithelial cells(PTECs)is considered a central event in the pathogenesis of chronic kidney disease(CKD)and deregulated repair processes of PTECs result in epithelialemesenchymal transiti...The damage of proximal tubular epithelial cells(PTECs)is considered a central event in the pathogenesis of chronic kidney disease(CKD)and deregulated repair processes of PTECs result in epithelialemesenchymal transition(EMT),which in turn aggravates tubular injury and kidney fibrosis.In this study,we firstly revealed that the reduction of TTC36 is associated with unilateral ureteral obstruction(UUO)-induced CKD;besides,ablation of TTC36 attenuated tubular injury and subsequent EMT in UUO-treated mice kidneys.Consistently,TTC36 overexpression promoted EMT in TGF-β1-induced HK2 cells.Moreover,TTC36 elevated the protein expression of CEBPB,which was involved in the regulation of TGF-β/SMAD3 signaling,and augmented SMAD3 signaling and downstream genetic response were reduced by CEBPB silencing.Collectively,our results uncovered that TTC36 deficiency plays a protective role in tubular injury and renal fibrosis triggered by UUO;further,TTC36 overexpression exacerbated TGF-β/SMAD3 signaling via elevating the stability of SMAD3 and CEBPB,suggesting that TTC36 inhibition may be a potential strategy in the therapy of obstructive nephropathy.展开更多
文摘AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule(EpCAM)(E-CTC), the mesenchymal cell markers vimentin and twist(M-CTC), or both(E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio(NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage(P < 0.01) and distant metastasis(P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation(P < 0.01).CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.
基金Supported by National Science Foundation of China,No.31471147
文摘Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition(EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.
基金Supported by the National Natural Science Foundation of China,No.81972005 and 82172339the Natural Science Foundation of Shandong Province,No.ZR2020MH238Shandong Medical and Health Technology Development Project,No.2018WS327.
文摘BACKGROUND As one of the most common tumors,gastric cancer(GC)has a high mortality rate,since current examination approaches cannot achieve early diagnosis.Fusobacterium nucleatum(Fn)primarily colonized in the oral cavity,has been reported to be involved in the development of gastrointestinal tumor.Until now,little is known about the relationship between salivary Fn and GC.AIM To determine whether salivary Fn could be a biomarker to diagnose GC and explore the influence of Fn on GC cells.METHODS The abundance of Fn in saliva was quantified by droplet digital polymerase chain reaction in 120 GC patients,31 atrophic gastritis(AG)patients,35 non-AG(NAG)patients,26 gastric polyp(GP)patients,and 20 normal controls(NC)from Qilu Hospital of Shandong University from January 2019 to December 2020.Receiver operating characteristic(ROC)curve analysis was performed to evaluate the diagnostic value of Fn as well as traditional serum tumor markers,including carcinoembryonic antigen(CEA),carbohydrate antigen(CA)19-9,and CA72-4.Transwell assay and wound-healing assay were conducted to assess the influence of Fn infection on GC cells.The expression of epithelial-mesenchymal transition(EMT)markers was detected using western blot assay.RESULTS We found that the level of salivary Fn in GC patients was significantly increased compared with those in AG,NAG,and GP patients and NC(P<0.001).ROC curve analysis showed a favorable capability of Fn(73.33% sensitivity;82.14%specificity;area under the curve:0.813)in GC diagnosis,which was superior to that of CEA,CA19-9,CA72-4,ferritin,and sialic acid.The Fn level in saliva of GC patients was increased as the TNM stage increased.GC patients with lymph node metastasis had higher Fn levels than those without metastasis.Both transwell and wound-healing assays indicated that Fn infection promoted the migration and invasion of GC cells.Western blot analysis showed that Fn infection decreased the expression of E-cadherin and increased the expressions of N-cadherin,vimentin,and snail.CONCLUSION Fn abundance in saliva could be used as a promising biomarker to diagnose GC,and Fn infection could promote GC metastasis by accelerating the EMT process.
基金This work is supported by a Schwab Foundation Grant and the James F.Hardymon Endowment in Urologic Research at the University of Kentucky(NK,PJH)the University of Kentucky Summer Undergraduate Research Experience in Environmental Health Sciences(SURES)program(HD).
文摘The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.
基金Supported by Shanghai Shenkang Hospital Development Center Three-Year Action Plan for Difficult Diseases Precision Treatment Project,No.16CR2022APudong New Area Joint Research Project,No.PW2017D-1+1 种基金hanghai Shenkang Hospital Development Center Technology Joint Promotion Project,No.SHDC12016236Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Training fund,No.PYMDT-003
文摘BACKGROUND Tumor budding,is a promising prognostic hallmark in many cancers,and can help us better assess the degree of malignancy in gastric cancer(GC)and in colorectal cancer.In the past few years,several articles on the relationship between tumor budding and GC have been published,but different results have been observed.As the relationship between tumor budding and GC remains controversial,we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis.AIM To systematically evaluate the prognostic and pathological impact of tumor budding in GC.METHODS Literature searches were conducted in the PubMed,Cochrane Library,EMBASE and Web of Science databases,and 7 cohort studies involving 2178 patients met our criteria and included in the analysis.The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding,and the cut-off values for tumor budding varied across the included studies.The hazard ratios(HRs)with 95%confidence intervals(CIs)were calculated to estimate the impact of tumor budding on overall survival(OS)in GC patients.The odds ratios(ORs)with 95%CIs were used to determine the correlation between tumor budding and pathological parameters(tumor stage,tumor differentiation,lymphovascular invasion,lymph node metastasis)of GC.RESULTS Seven studies involving 2178 patients were included in the meta-analysis.The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage(OR=6.63,95%CI:4.01-10.98,P<0.01),tumor differentiation(OR=3.74,95%CI:2.68-5.22,P<0.01),lymphovascular invasion(OR=7.85,95%CI:5.04-12.21,P<0.01),and lymph node metastasis(OR=5.75,95%CI:3.20-10.32,P<0.01).Moreover,high-grade tumor budding predicted a poor 5-year OS(HR=1.79,95%CI:1.53-2.05,P<0.01)in patients with GC and an adverse 5-year OS(HR=1.93,95%CI:1.45-2.42,P<0.01)in patients with intestinal-type GC.CONCLUSION High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.
基金supported by the Technology Development Program of Shanghai Pudong New District(No.PKJ2021-Y34)the Excellent Young Medical Talent Training Program of Pudong Health Commission of Shanghai(No.PWRq2022-18).
文摘Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to PD.Methods:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6J mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF.HE and Masson staining were performed to evaluate the extent of PF.The therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,Western blotting,and peritoneal function analyses.Epithelial-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%PDF.Cells were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment group.Cell Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells.Results:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs.The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD mice.We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice.Compared with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response,with markedly increased peritoneal thickness and higher expression ofα-SMA,collagen-I,fibronectin,and ECM1.The mice with PD showed decreased miR-27a-3p.Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment,while PF and mesothelial damage were significantly ameliorated.Additionally,markers of fibrosis(α-SMA,collagen-I,fibronectin,ECM1)and profibrotic cytokines(TGF-β1,PDGF)were downregulated at the mRNA and protein levels after BMSC-Exos treatment.In HMrSV5 cells,BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF.Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin(epithelial marker)and decreased expression ofα-SMA,Snail,and vimentin(mesenchymal markers)compared to those of the 4.25%PDF-treated cells.Importantly,a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p.TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos.Conclusion:The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.
基金Supported by Shandong Province Medicine and Health Science and Technology Development Plan Project,No. 2019WS477
文摘BACKGROUND Gastric cancer(GC)is considered as one of the most widespread malignancies.Emerging evidence has shown that lncRNAs can function as important oncogenes or tumor suppressors during GC progression.AIM To investigate the effect and mechanism of lncRNA cancer susceptibility 20(CASC20)in the proliferation and metastasis of GC cells.METHODS Data mining and clinical samples were used to evaluate the expression of CASC20 in GC and adjacent tissues.CASC20 was down-regulated in GC cells by shortinterfering RNA.Cell proliferation was evaluated by CCK-8 assay,and cell migration and invasion were detected by wound healing and Transwell assays.The expressions of proteins related to epithelial-mesenchymal transition were detected by western blot assay.RESULTS The expression of CASC20 was increased in GC tumor tissues and various GC cell lines.High CASC20 expression was correlated with a high risk of lymphatic metastasis and poor prognosis in GC patients.In vitro assays showed that silencing CASC20 reduced cell proliferation,migration,and invasion in GC cells.Mechanistic studies revealed that CASC20 exhibits oncogenic functions by regulating MEMO1 expression through competitive endogenous binding to miR-143-5p,leading to induction of epithelial-mesenchymal transition.CONCLUSION Our findings indicate that CASC20 serves as a tumor promoter by regulating metastasis in GC via the miR-143-5p/MEMO1 axis.CASC20 may be a potential therapeutic target for GC.
基金the Key Project of Science and Technology of Xinxiang,No.GG2020027the Health Commission of Henan Province of China,No.SBGJ202102188.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC),the predominant type of esophageal cancer,has a 5-year survival rate less than 20%.Although the cause of poor prognosis is the high incidence and mortality of ESCC,the high rate of metastasis after esophageal cancer surgery is the main cause of death after the surgery.Bromodomain-containing protein 4(BRD4),an epigenetic reader of chromatinacetylated histones in tumorigenesis and development,plays an essential role in regulating oncogene expression.BRD4 inhibition and BRD4 inhibition-based treatment can potentially suppress ESCC growth.However,the effects and mechanisms of action of BRD4 on ESCC cell migration remain unclear.AIM To explore the effect of BRD4 on cell migration of ESCC in vitro and its possible molecular mechanism.METHODS Human ESCC cell lines KYSE-450 and KYSE-150 were used.The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay was performed to examine cell proliferation,and the transwell migration assay was conducted to test ESCC cell migration.JQ1,a BRD4 inhibitor,was applied to cells,and BRD4 siRNA was transfected into ESCC cells to knockdown endogenous BRD4.GFP-RFP-LC3 adenovirus was infected into ESCC cells to evaluate the effect of JQ1 on autophagy.Western blotting was performed to determine the protein levels of BRD4,E-cadherin,vimentin,AMP-activated protein kinase(AMPK),and p-AMPK.RESULTS BRD4 was either downregulated by small interfering RNA or pretreated with JQ1 in ESCC cells,leading to increased tumor migration in ESCC cells in a dose-and time-dependent manner.Inhibition of BRD4 not only significantly suppressed cell proliferation but also strongly increased cell migration by inducing epithelial-mesenchymal transition(EMT).The protein expression of vimentin was increased and E-cadherin decreased in a dose-dependent manner,subsequently promoting autophagy in KYSE-450 and KYSE-150 cells.Pretreatment with JQ1,a BRD4 inhibitor,inhibited BRD4-induced LC3-II activation and upregulated AMPK phosphorylation in a dosedependent manner.Additionally,an increased number of autophagosomes and autolysosomes were observed in JQ1-treated ESCC cells.The autophagy inhibitor 3-methyladenine(3-MA)reversed the effects of BRD4 knockdown on ESCC cell migration and blocked JQ1-induced cell migration.3-MA also downregulated the expression of vimentin and upregulation E-cadherin.CONCLUSION BRD4 inhibition enhances cell migration by inducing EMT and autophagy in ESCC cells via the AMPK-modified pathway.Thus,the facilitating role on ESCC cell migration should be considered for BRD4 inhibitor clinical application to ESCC patients.
基金Supported by the 63th Postdoctoral Science Foundation of China(No.2018M632487)General Natural Science ProjectsDepartment of Education,Zhejiang Province,China(No.Y201636718)
文摘AIM: To evaluate the effects of epidermal growth factor(EGF) on transforming growth factor-beta1(TGF-β1)-induced epithelial-mesenchymal transition(EMT) in human corneal epithelial cells(HCECs). METHODS: HCECs were cultured and treated with TGF-β1 for establishing the model of EMT in vitro. Biological effect of EGF on TGF-β1-induced EMT was evaluated. Proteins and m RNAs expression changes of E-cadherin, N-cadherin and Fibronectin(EMT-relative markers) after TGF-β1 or TGF-β1 combined EGF treatment were detected by Western blot and RT-PCR, respectively. Viability and migration of HCECs were measured by CCK-8, transwell cell migration assay and cell scratch wound healing assay. Activation of Smad2, ERK, p38, JNK and Akt signaling pathways were evaluated by Western blot. Inhibitors of relevant signaling pathways were added to the HCECs to explore the key signal mechanism.RESULTS: With treatment of TGF-β1 only, three EMTrelative proteins and m RNA expression showed that EMT up-regulated in a concentration-dependent and time-dependent manner, with significantly decreasing cell viability(TGF-β1≥5 ng/m L, P<0.05) and increasing cell migration(TGF-β1≥5 ng/m L, P<0.01). The phosphorylation of Smad2 and p38 was a key process of TGF-β1-induced EMT. Meanwhile, EMT-relative proteins and m RNA expression showed that EGF inhibited TGF-β1-indued EMT, with significantly increasing cell viability(EGF≥10 ng/m L, P<0.01). It was noteworthy that EGF significantly enhanced cell migration although EMT was inhibited(EGF≥10 ng/m L, P<0.01), and the blockage of p38(by SB202190, a p38 inhibitor) was a potential mechanism of this phenomenon. CONCLUSION: EGF inhibits TGF-β1-induced EMT via suppressive p38, and promotes cells proliferation and migration in a non-EMT process by inhibiting p38 pathway.
基金The author apologizes to my colleagues for my inability to refer many important studies due to the limitation of the length.I thank Dr.Osamu Ogawa for helpful discussions.This work was supported by Grants-in-aid for Scientific Research to the author from Japan Society for the Promotion of Science(25713055).
文摘Management of unresectable urothelial cancer(UC)has been a clinical challenge for decades.While drug resistance is a key issue,precise understanding of biology of UC metastasis is another challenge for the improvement of treatment outcome of UC patients.Introduction of the cell biology concepts including epithelial-mesenchymal transition(EMT)and cancer stemness seems to explain UC metastasis.Molecular genetics based on gene expression profiling,next generation sequencing,and explosion of non-coding RNA world has opened the door to intrinsic molecular subtyping of UC.Next steps include,based on the recently accumulated understanding,the establishment of novel disease models representing UC metastasis in various experimental platforms,particularly in vivo animal systems.Indeed,novel knowledge molecular genetics has not been fully linked to the modeling of UC metastasis.Further understanding of bladder carcinogenesis is needed particularly with regard to cell of origin related to tumor characteristics including driver gene alterations,pathological differentiations,and metastatic ability.Then we will be able to establish better disease models,which will consequently lead us to further understanding of biology and eventually the development of novel therapeutic strategies for UC metastasis.
基金National Natural Science Foundation of China,No.81502304Science and Technology Projects of Quzhou,No.2018K20Suitable Technology Promotion Center New Technology and Product Research and Development Projects,No.2019329288
文摘A recent publication highlights the importance of high yes-associated protein(YAP) expressing cells in liver regeneration following partial hepatectomy.Although the names of the cell populations described in these articles [hybrid periportal hepatocytes(HybHP) or epithelial-mesenchymal transition(EMT)-reprogrammed hepatocytes] are not identical, they all express high levels of YAP.We hypothesize that the HybHP and EMT-reprogrammed hepatocytes might be a similar cell population. Hippo signaling is the primary pathway that regulates YAP activity. According to the contribution of these two types of cells to liver regeneration and the high YAP expression, Hippo-YAP signaling activation may be a common regulatory pathway experienced by cells undergoing dedifferentiation and reactivating proliferative activity during liver regeneration.Although no evidence has shown that HybHP cells contribute to hepatocellular carcinoma in mouse models, we can not rule out the possibility that these highly regenerative cells can further develop into tumor cells when they acquire mutations caused by viral infection or other risk factors like alcohol. The detailed mechanistic insight of the regulation of YAP expression and activity in HybHP(or other types of cells contributing to liver regeneration) is unknown. We hypothesize that liver regeneration under various conditions will eventually lead to divergent consequences, likely due to the duration of YAP activation regulated by Hippo-large tumor suppressor 1 and 2 pathway in a context-and cell typedependent manner.
文摘Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"in the AGS cells wound healing assay was incorrectly inserted during the preparation of the submission;the correct figure is provided in this correction.
基金Supported by the Key Research&Development Program of Shaanxi Province(No.2022SF-311,No.2024SFYBXM-328,No.2024SF-YBXM-325)the Natural Science Basic Research Program of Shaanxi Province,China(No.2021JQ-385).
文摘AIM:To evaluate the effect of bone morphogenetic protein-6(BMP-6)on transforming growth factor(TGF)-β_(2)-induced epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE).METHODS:Adult retinal pigment epithelial cell line(ARPE-19)were randomly divided into control,TGF-β_(2)(5μg/L),and BMP-6 small interfering RNA(siRNA)group.The cell morphology was observed by microscopy,and the cell migration ability were detected by Transwell chamber.The EMT-related indexes and BMP-6 protein levels were detected by Western blotting.Furthermore,a BMP-6 overexpression plasmid was constructed and RPE cells were divided into the control group,TGF-β_(2)+empty plasmid group,BMP-6 overexpression group,and TGF-β_(2)+BMP-6 overexpression group.The EMT-related indexes and extracellular regulated protein kinases(ERK)protein levels were detected.RESULTS:Compared with the control group,the migration of RPE cells in the TGF-β_(2) group was significantly enhanced.TGF-β_(2) increased the protein expression levels ofα-smooth muscle actin(α-SMA),fibronectin and vimentin but significantly decreased the protein levels of E-cadherin and BMP-6(P<0.05)in RPE.Similarly,the migration of RPE cells in the BMP-6 siRNA group was also significantly enhanced.BMP-6 siRNA increased the protein expression levels ofα-SMA,fibronectin and vimentin but significantly decreased the protein expression levels of E-cadherin(P<0.05).Overexpression of BMP-6 inhibited the migration of RPE cells induced by TGF-β_(2) and prevented TGF-β_(2) from affecting EMT-related biomarkers(P<0.05).CONCLUSION:BMP-6 prevents the EMT in RPE cells induced by TGF-β_(2),which may provide a theoretical basis for the prevention and treatment of proliferative vitreoretinopathy.
基金National Natural Science Foundation of China,Grant/Award Numbers:82203709,82173216,82372950,82372951China Postdoctoral Science Foundation,Grant/Award Number:2022M710895Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2024A1515013031。
文摘Background:Adaptative desaturation in fatty acid(FA)is an emerging hallmark of cancer metabolic plasticity.Desaturases such as stearoyl-CoA desaturase(SCD)and fatty acid desaturase 2(FADS2)have been implicated in multiple cancers,and their dominant and compensatory effects have recently been highlighted.However,how tumors initiate and sustain their self-sufficient FA desaturation to maintain phenotypic transition remains elusive.This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression.Methods:The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts,which guided subsequent functional and mechanistic investigations.The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines.Specific desaturation activities were characterized through various isomer-resolved lipidomics methods and sensitivity assays using desaturase inhibitors.In-situ lipid profilingwas conducted using multiplex stimulated Raman scattering imaging.Functional assays were performed both in vitro and in vivo,with RNA-sequencing employed for the mechanism verification.Results:After integration of the RNA-protein-metabolite levels,the data revealed that a reprogramming fromSCD-dependent to FADS2-dependent desaturation was linked to cancer epithelial-mesenchymal transition(EMT)and progression in both patients and cell lines.FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity.A FADS2/β-catenin selfreinforcing feedback loop facilitated the degree of lipid unsaturation,membrane fluidity,metastatic potential and EMT signaling.Moreover,SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate-activated protein kinase activation.Notably,this desaturation reprogramming increased transforming growth factor-β2,effectively sustaining aggressive phenotypes and metabolic plasticity during EMT.Conclusions:These findings revealed a metabolic reprogramming from SCDdependent to FADS2-dependent desaturation during cancer EMT and progression,which concurrently supports EMT plasticity.Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.
文摘Extracellular vesicles from highly metastatic tumor cells have been shown to mediate epithelial-mesenchymal transition(EMT)-related events in recipient cells.In endometrial epithelial cells,EMT processes are known to be involved in the development of adenomyosis.We aimed to investigate whether adenomyosis-derived extracellular vesicles(AMEVs)are able to induce an EMT process in endometrial epithelial cells.In this study,AMEVs were isolated from patients with adenomyosis and characterized by transmission electron microscopy,Western blot,and nanoparticle tracking.Primary endometrial epithelial cells(EECs)were derived from normal endometrium tissues from patients with leiomyoma and co-cultured with AMEVs in vitro.AMEV uptake was examined by fluorescence confocal microscopy.The invasion of EECs was confirmed by Transwell assay.Immunohistochemistry,Western blot,and qRT-PCR were performed on EECs to illustrate the expression levels of cytokeratin 19,E-cadherin,vimentin,and zinc finger E-boxbinding homeobox 1(ZEB1).The results indicated that the cellular fluorescence intensity gradually increased after 48 h of co-culture,but decreased after 72 h.After co-culturing with AMEVs for 72 h,EECs expressed significantly lower levels of cytokeratin 19 and E-cadherin,and significantly higher levels of vimentin and ZEB1.Together these results demonstrated that AMEVs induce an EMT process and enhance the invasion of EECs.These changes may contribute to the pathogenesis and progression of adenomyosis.
基金We apologize to the many contributors to this field whose work are important while we were unable to cite due to space limitation.Our study is supported by the grants from National Institutes of Health(NIH)(RO1s CA125454 and CA188118)Department of Defense(DOD)Breakthrough Award(BC140733P1)Mary Kay Ash Foundation(to B.P.Zhou),and the Basic Public Welfare Research Program of Zhejiang Province(LGF18H290003 to Y.Wang).
文摘Epithelial-mesenchymal Transition(EMT)is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance,metastasis,and recurrence.This dynamic and reversible events is governed by a network of EMT-transcription factors(EMT-TFs)through epigenetic regulation.Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates;this suggests that EMT is subjected to the metabolic regulation.Conversely,EMT rewires metabolic program to accommodate cellular changes during EMT.Here we summarize the latest findings regarding the epigenetic regulation of EMT,and discuss the mutual interactions among metabolism,epigenetic regulation,and EMT.Finally,we provide perspectives of how this interplay contributes to cellular plasticity,which may result in the clinical manifestation of tumor heterogeneity.
基金This work was supported by the National Natural Science Foundation of China(No.81873932,81802549)the Scientific and Technological Research Program of Chongqing Municipal Education Commission(No.KJQN202000438)Chongqing Science and Technology Commission(No.cstc2019jscx-dxwtBX0032).
文摘The damage of proximal tubular epithelial cells(PTECs)is considered a central event in the pathogenesis of chronic kidney disease(CKD)and deregulated repair processes of PTECs result in epithelialemesenchymal transition(EMT),which in turn aggravates tubular injury and kidney fibrosis.In this study,we firstly revealed that the reduction of TTC36 is associated with unilateral ureteral obstruction(UUO)-induced CKD;besides,ablation of TTC36 attenuated tubular injury and subsequent EMT in UUO-treated mice kidneys.Consistently,TTC36 overexpression promoted EMT in TGF-β1-induced HK2 cells.Moreover,TTC36 elevated the protein expression of CEBPB,which was involved in the regulation of TGF-β/SMAD3 signaling,and augmented SMAD3 signaling and downstream genetic response were reduced by CEBPB silencing.Collectively,our results uncovered that TTC36 deficiency plays a protective role in tubular injury and renal fibrosis triggered by UUO;further,TTC36 overexpression exacerbated TGF-β/SMAD3 signaling via elevating the stability of SMAD3 and CEBPB,suggesting that TTC36 inhibition may be a potential strategy in the therapy of obstructive nephropathy.
