BACKGROUND Lymphovascular invasion(LVI)and perineural invasion(PNI)are associated with decreased survival in colorectal cancer(CRC),but its significance in N1c stage remains to be clearly defined.AIM We retrospectivel...BACKGROUND Lymphovascular invasion(LVI)and perineural invasion(PNI)are associated with decreased survival in colorectal cancer(CRC),but its significance in N1c stage remains to be clearly defined.AIM We retrospectively identified 107 consecutive patients who had CRC with N1c disease radically resected at our hospital.Tumors were reviewed for LVI and PNI by one pathologist blinded to the patients’outcomes.Disease-free survival(DFS),overall survival(OS)and cancer-specific survival(CSS)were determined using the Kaplan-Meier method,with LVI and PNI prognosis differences determined by multivariate analysis using the Cox multiple hazards model.Results were compared using log-rank test.The receiver operating characteristic(ROC)curve was used to evaluate the prognostic predictive ability.RESULTS The median follow-up time was 63.17(45.33-81.37)months for DFS,with 33.64%(36/107)of patients experiencing recurrence;21.5%of tumors were found to be LVI positive and 44.9%PNI positive.The 5-year DFS rate was greater for patients with LVI-negative tumors compared with LVI-positive tumors(74.0%vs 35.6%),and PNI was similar(82.5%vs 45.1%).On multivariate analysis,LVI[hazard ratio(HR)=3.368,95%confidence interval(CI):1.628-6.966,P=0.001]and PNI(HR=3.055,95%CI:1.478-6.313,P=0.002)were independent prognostic factors for DFS.All patients could be divided into three groups of patients with different prognosis according to LVI and PNI.The 5-year ROC curve for LVI,PNI and their combination prediction of DFS was 0.646,0.709 and 0.759,respectively.Similar results were seen for OS and CSS.CONCLUSION LVI and PNI could serve as independent prognostic factors of outcomes in N1c CRC patients.Patients with LVI or PNI should be given more attention during treatment.展开更多
BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complicat...BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications.However,the function of m6A methyltransferase Wilms tumor 1-associated protein(WTAP)in diabetic wound healing remains elusive.AIM To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing.METHODS Human umbilical vein endothelial cells(HUVECs)were induced with high glucose(HG)to establish in vitro cell model.Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes,and full-thickness excision was made to mimic diabetic wound healing.HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1(DNMT1)overexpression vectors.Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays.In vitro angiogenesis was measured using a tube formation experiment.The images of wounds were captured,and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson’s trichrome staining.RESULTS The expression of several m6A methyltransferases,including METTL3,METTL14,METTL16,KIAA1429,WTAP,and RBM15,were measured.WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control.WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG.The unclosed wound area of mice was smaller in WTAP knockdowntreated mice than in control mice at nine days post-wounding,along with enhanced re-epithelialization rate and collagen deposition.The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs.The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs.Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs.CONCLUSION WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.展开更多
BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.S...BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.展开更多
基金Supported by the National High Level Hospital Clinical Research Funding,No.2023-NHLHCRF-BQ-32 and No.2023-NHLHCRFYYPPLC-ZR-13the Elite Medical Professionals Project of China-Japan Friendship Hospital,No.ZRJY2024-GG01.
文摘BACKGROUND Lymphovascular invasion(LVI)and perineural invasion(PNI)are associated with decreased survival in colorectal cancer(CRC),but its significance in N1c stage remains to be clearly defined.AIM We retrospectively identified 107 consecutive patients who had CRC with N1c disease radically resected at our hospital.Tumors were reviewed for LVI and PNI by one pathologist blinded to the patients’outcomes.Disease-free survival(DFS),overall survival(OS)and cancer-specific survival(CSS)were determined using the Kaplan-Meier method,with LVI and PNI prognosis differences determined by multivariate analysis using the Cox multiple hazards model.Results were compared using log-rank test.The receiver operating characteristic(ROC)curve was used to evaluate the prognostic predictive ability.RESULTS The median follow-up time was 63.17(45.33-81.37)months for DFS,with 33.64%(36/107)of patients experiencing recurrence;21.5%of tumors were found to be LVI positive and 44.9%PNI positive.The 5-year DFS rate was greater for patients with LVI-negative tumors compared with LVI-positive tumors(74.0%vs 35.6%),and PNI was similar(82.5%vs 45.1%).On multivariate analysis,LVI[hazard ratio(HR)=3.368,95%confidence interval(CI):1.628-6.966,P=0.001]and PNI(HR=3.055,95%CI:1.478-6.313,P=0.002)were independent prognostic factors for DFS.All patients could be divided into three groups of patients with different prognosis according to LVI and PNI.The 5-year ROC curve for LVI,PNI and their combination prediction of DFS was 0.646,0.709 and 0.759,respectively.Similar results were seen for OS and CSS.CONCLUSION LVI and PNI could serve as independent prognostic factors of outcomes in N1c CRC patients.Patients with LVI or PNI should be given more attention during treatment.
文摘BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications.However,the function of m6A methyltransferase Wilms tumor 1-associated protein(WTAP)in diabetic wound healing remains elusive.AIM To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing.METHODS Human umbilical vein endothelial cells(HUVECs)were induced with high glucose(HG)to establish in vitro cell model.Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes,and full-thickness excision was made to mimic diabetic wound healing.HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1(DNMT1)overexpression vectors.Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays.In vitro angiogenesis was measured using a tube formation experiment.The images of wounds were captured,and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson’s trichrome staining.RESULTS The expression of several m6A methyltransferases,including METTL3,METTL14,METTL16,KIAA1429,WTAP,and RBM15,were measured.WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control.WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG.The unclosed wound area of mice was smaller in WTAP knockdowntreated mice than in control mice at nine days post-wounding,along with enhanced re-epithelialization rate and collagen deposition.The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs.The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs.Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs.CONCLUSION WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.
基金Supported by Natural Science Foundation of Guangdong Province,No.2022A1515012346.
文摘BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.
