Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on...Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.展开更多
Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperat...Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperated with MaHDA1 to precisely regulate the transcription of ripening-associated genes via histone deacetylation.However,whether MaERF11 is subjected to post-translational modification during banana ripening is largely unknown.In this study,we found that MaERF11 targeted a subset of starch degradation-related genes using the DNA affinity purification sequence(DAP-Seq)approach.Electrophoretic mobility shift assay(EMSA)and dual-luciferase reporter assay(DLR)demonstrated that MaERF11 could specifically bind and repress the expression of the starch degradation-related genes MaAMY3,MaBAM2 and MaGWD1.Further analyses of yeast two-hybrid(Y2H),bimolecular fluorescence complementation(BiFC)and Luciferase complementation imaging(LCI)assays indicated that MaERF11 interacted with the ubiquitin E3 ligase MaRFA1,and this interaction weakened the MaERF11-mediated transcriptional repression capacity.Collectively,our results suggest an additional regulatory layer in which MaERF11 regulates banana fruit ripening and expands the regulatory network in fruit ripening at the post-translational modification level.展开更多
BACKGROUND It is critical to explore effective therapeutic targets for improving the survival rate of patients with hepatocellular carcinoma(HCC).Although many studies have focused on flotillin-1(FLOT1)as a lipid raft...BACKGROUND It is critical to explore effective therapeutic targets for improving the survival rate of patients with hepatocellular carcinoma(HCC).Although many studies have focused on flotillin-1(FLOT1)as a lipid raft-associated protein that regulates the activation of some proteins or kinases to promote tumor cell survival and proliferation,few studies have explored the regulation of Golgi apparatus function.AIM To investigate the molecular mechanism through which FLOT1 activates the Golgi stress response downstream of transcription factor E3(TFE3),thereby promoting the progression of HCC.METHODS FLOT1 expression in HCC tissue,HCC cell lines,and nude mouse tumor models was assessed.The impact of FLOT1 silencing or its overexpression on the proliferation of HCC cells was studied.CCK-8,flow cytometry,and transwell assays were used to assess the proliferation,cell cycle,migration,and invasion abilities of HCC cells.A dual-luciferase reporter assay was used to study the effect of FLOT1 on the transcriptional activity of the downstream Golgi apparatus stress element promoter of TFE3.Western blotting,co-immunoprecipitation,and immunofluorescence staining were employed to detect relevant proteins.RESULTS High FLOT1 expression was correlated with a poor prognosis in patients with HCC.The knockdown of FLOT1 suppressed the proliferation,migration,and invasion of HCC cells and promoted their apoptosis.Xenograft assays revealed that FLOT1 knockdown inhibited HCC tumorigenesis in vivo.Mechanistically,FLOT1 inhibited the expression of mechanistic target of rapamycin complex 1/2 proteins through ubiquitination and downstream effector p-S6 kinase-T389,leading to the dephosphorylation and nuclear translocation of TFE3 and promotion of Golgi stress-mediated responses,ultimately resulting in HCC progression.CONCLUSION FLOT1 recruits and inhibits mechanistic target of rapamycin complex 1/2,causing dephosphorylation and TFE3 nuclear translocation,thereby activating the Golgi stress response and further promoting the proliferation,migration,and invasion capabilities of HCC cells.These results underscore the potential of FLOT1 as a promising therapeutic target for HCC.展开更多
In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)pro...In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81974441 and 82203619)the Science and Technology Planning Project of Shenzhen Municipality(Nos.JCYJ20190814105619048 and JCYJ20220530154202005)。
文摘Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.
基金financially supported by the National Natural Science Foundation of China(Grant Nos.31830071,32202561)the earmarked fund for CARS(Grant No.CARS-31)。
文摘Banana fruit ripening is a highly regulatory process involving various layers consisting of transcriptional regulation,epigenetic factor,and post-translational modification.Previously,we reported that MaERF11 cooperated with MaHDA1 to precisely regulate the transcription of ripening-associated genes via histone deacetylation.However,whether MaERF11 is subjected to post-translational modification during banana ripening is largely unknown.In this study,we found that MaERF11 targeted a subset of starch degradation-related genes using the DNA affinity purification sequence(DAP-Seq)approach.Electrophoretic mobility shift assay(EMSA)and dual-luciferase reporter assay(DLR)demonstrated that MaERF11 could specifically bind and repress the expression of the starch degradation-related genes MaAMY3,MaBAM2 and MaGWD1.Further analyses of yeast two-hybrid(Y2H),bimolecular fluorescence complementation(BiFC)and Luciferase complementation imaging(LCI)assays indicated that MaERF11 interacted with the ubiquitin E3 ligase MaRFA1,and this interaction weakened the MaERF11-mediated transcriptional repression capacity.Collectively,our results suggest an additional regulatory layer in which MaERF11 regulates banana fruit ripening and expands the regulatory network in fruit ripening at the post-translational modification level.
基金Supported by the National Natural Science Foundation of China,No.82203806the General Hospital of Western Theater Command Project Funding,No.2024-YGJC-B10.
文摘BACKGROUND It is critical to explore effective therapeutic targets for improving the survival rate of patients with hepatocellular carcinoma(HCC).Although many studies have focused on flotillin-1(FLOT1)as a lipid raft-associated protein that regulates the activation of some proteins or kinases to promote tumor cell survival and proliferation,few studies have explored the regulation of Golgi apparatus function.AIM To investigate the molecular mechanism through which FLOT1 activates the Golgi stress response downstream of transcription factor E3(TFE3),thereby promoting the progression of HCC.METHODS FLOT1 expression in HCC tissue,HCC cell lines,and nude mouse tumor models was assessed.The impact of FLOT1 silencing or its overexpression on the proliferation of HCC cells was studied.CCK-8,flow cytometry,and transwell assays were used to assess the proliferation,cell cycle,migration,and invasion abilities of HCC cells.A dual-luciferase reporter assay was used to study the effect of FLOT1 on the transcriptional activity of the downstream Golgi apparatus stress element promoter of TFE3.Western blotting,co-immunoprecipitation,and immunofluorescence staining were employed to detect relevant proteins.RESULTS High FLOT1 expression was correlated with a poor prognosis in patients with HCC.The knockdown of FLOT1 suppressed the proliferation,migration,and invasion of HCC cells and promoted their apoptosis.Xenograft assays revealed that FLOT1 knockdown inhibited HCC tumorigenesis in vivo.Mechanistically,FLOT1 inhibited the expression of mechanistic target of rapamycin complex 1/2 proteins through ubiquitination and downstream effector p-S6 kinase-T389,leading to the dephosphorylation and nuclear translocation of TFE3 and promotion of Golgi stress-mediated responses,ultimately resulting in HCC progression.CONCLUSION FLOT1 recruits and inhibits mechanistic target of rapamycin complex 1/2,causing dephosphorylation and TFE3 nuclear translocation,thereby activating the Golgi stress response and further promoting the proliferation,migration,and invasion capabilities of HCC cells.These results underscore the potential of FLOT1 as a promising therapeutic target for HCC.
基金Supported by Italian Association for Cancer Research(AIRC),No.21956Italian Ministry of Health-5×1000 funds 2023.
文摘In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.
