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SUMMARY: Esophageal cancer is one of the most aggressive gastrointestinal cancers. Invasion and metastasis are the main causes of poor prognosis of esophageal cancer. SPRY2 has been reported to exert promoting effects in human cancers, which controls signal pathways including PI3K/AKT and MAPKs. However, the expression of SPRY2 in esophageal squamous cell carcinoma (ESCC) and its underlying mechanism remain unclear. In the present study, we aimed to investigate the detailed role of SPRY2 in the regulation of cell proliferation, invasion and ERK/AKT signaling pathway in ESCC. It was identified that the expression level of SPRY2 in ESCC was remarkably decreased compared with normal tissues, and it was related to clinicopathologic features and prognosis ESCC patients. The upregulation of SPRY2 expression notably inhibited the proliferation, migration and invasion of Eca-109 cells. In addition, the activity of ERK /AKT signaling was also suppressed by the SPRY2 upregulation in Eca-109 cells. Our study suggests that overexpression of SPRY2 suppress cancer cell proliferation and invasion of by through suppression of the ERK/AKT signaling pathways in ESCC. Therefore, SPRY2 may be a promising prognostic marker and therapeutic target for ESCC.
El cáncer de esófago es uno de los cánceres gastrointestinales más agresivos. La invasión y la metástasis son las principales causas de mal pronóstico del cáncer de esófago. Se ha informado que SPRY2 ejerce efectos promotores en los cánceres humanos, que controla las vías de señales, incluidas PI3K/AKT y MAPK. Sin embargo, la expresión de SPRY2 en el carcinoma de células escamosas de esófago (ESCC) y su mecanismo subyacente aún no están claros. En el presente estudio, nuestro objetivo fue investigar el papel detallado de SPRY2 en la regulación de la proliferación celular, la invasión y la vía de señalización ERK/AKT en ESCC. Se identificó que el nivel de expresión de SPRY2 en ESCC estaba notablemente disminuido en comparación con los tejidos normales, y estaba relacionado con las características clínico-patológicas y el pronóstico de los pacientes con ESCC. La regulación positiva de la expresión de SPRY2 inhibió notablemente la proliferación, migración e invasión de células Eca-109. Además, la actividad de la señalización de ERK/AKT también fue suprimida por la regulación positiva de SPRY2 en las células Eca-109. Nuestro estudio sugiere que la sobreexpresión de SPRY2 suprime la proliferación y la invasión de células cancerosas mediante la supresión de las vías de señalización ERK/AKT en ESCC. Por lo tanto, SPRY2 puede ser un marcador de pronóstico prometedor y un objetivo terapéutico para la ESCC.
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Humanos , Neoplasias Esofágicas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteínas de Membrana/metabolismo , Imuno-Histoquímica , Biomarcadores Tumorais , Western Blotting , MAP Quinases Reguladas por Sinal Extracelular , Proliferação de Células , Proteínas Proto-Oncogênicas c-aktRESUMO
Objective To explore the relationship between p-FGFR1Y654 expression and clinical pathological characteristics of esophageal squamous cell carcinoma patients and its prognostic value.Methods Tumor tissue samples from 103 cases of esophageal squamous cell carcinoma and 58 normal esophageal tissues were surgically collected in the General Hospital of Western Theater between January 2017 and July 2020.The expression of p-FGFR1Y654 in the tissues was detected using immunohistochemical assay,and its correlation with relevant clinicopathological parameters and prognosis was analyzed.Results The expression of p-FGFR1Y654 in esophageal squamous cell carcinoma tissues was significantly higher than that in normal tissue(P＜0.01).Its expression level was closely related to overall survival(OS,P＜0.05),but not related to age,gender,tumor stage or tumor size.Multivariate COX regression analysis showed that N-stage was identified as an independent prognostic factor for recurrence free survival(RFS)in esophageal squamous cell carcinoma patients.Survival analysis indicated that patients with low expression of p-FGFR1Y654 had significantly higher RFS and OS than those with high expression(P=0.032,95％CI:1.08～4.65;P=0.004,95％CI:2.14-11.51).Conclusion p-FGFR1Y654 is highly expressed in esophageal squamous cell carcinoma tissue,and is associated with poor prognosis in these patients.p-FGFR1Y654 may be a potential therapeutic target for esophageal squamous cell carcinoma.
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In recent years, with the continuous development of biotechnology, liquid biopsy techno-logy has gradually become a research hotspot in the field of tumor research. As a non-invasive diagnostic method, liquid biopsy has great advantages compared with traditional methods. The liquid biopsy technology is precise, convenient, non-invasive and safe, and has an increasingly important clinical significance in the early diagnosis, treatment and prognosis assessment of esophageal squamous cell carcinoma.
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Objective:To investigate the efficacy of immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy for stage Ⅲ-ⅣA esophageal squamous cell carcinoma (ESCC) in the real world.Methods:The clinical data of 65 patients with stage Ⅲ-ⅣA ESCC treated by radical radiotherapy and chemotherapy from January 1, 2018 to December 31, 2022 in Hefei Cancer Hospital, Chinese Academy of Sciences were retrospectively analyzed. According to whether to undergo immune checkpoint inhibitor maintenance therapy after radical radiotherapy and chemotherapy, the patients were divided into a control group ( n=29) and an immune maintenance therapy group ( n=36) . The objective response rate (ORR) , progression-free survival (PFS) , and overall survival (OS) between the two groups were compared. Kaplan-Meier method was used to draw the survival curve accompanied with log-rank test. Cox regression model was used to conduct both univariate and multivariate analyses. Results:The ORR was 34.5% (10/29) in the control group and 61.1% (22/36) in the immune maintenance therapy group, with a statistically significant difference ( χ2=4.56, P=0.032) . The median PFS of control group and immune maintenance therapy group were 7.2 and 17.9 months, respectively, with a statistically significant difference ( χ2=7.86, P=0.005) . The median OS was 14.1 and 27.8 months, respectively, with a statistically significant difference ( χ2=5.40, P=0.020) . Univariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.28, P<0.001) and immune maintenance therapy ( HR=0.38, 95% CI: 0.17-0.88, P=0.024) were the influential factors of OS in ESCC patients treaded by radical chemoradiotherapy in stage Ⅲ-ⅣA. Multivariate analysis showed that, objective response ( HR=0.09, 95% CI: 0.03-0.29, P<0.001) and immune maintenance therapy ( HR=0.40, 95% CI: 0.17-0.92, P=0.032) were the independent influencing factors for OS in ESCC patients treaded by radical chemoracial therapy in stage Ⅲ-ⅣA. The incidence of adverse reactions was 22.22% (8/36) in the immune maintenance therapy group and 10.34% (3/29) in the control group, with no statistically significant difference ( χ2=1.61, P=0.204) . All the adverse reactions were grade 1-2, and the symptoms were relieved after symptomatic treatment. Conclusion:Maintenance therapy with immune checkpoint inhibitors after radical chemoradiotherapy of stage Ⅲ-ⅣA ESCC can significantly improve the prognosis of patients with good safety.
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Objective·To compare the prognostic effects of radical resection of esophageal cancer,concurrent chemoradiotherapy and simple follow-up observation on the prognosis of patients with T1b invasion of superficial esophageal squamous cell carcinoma after endoscopic submucosal dissection(ESD).Methods·From May 2016 to May 2021,the clinical data of 67 patients with esophageal squamous cell carcinoma who were pathologically confirmed as pT1b after ESD and treated in Shanghai Chest Hospital were retrospectively analyzed.According to the additional treatment after ESD,the patients were divided into additional surgery group(S group),chemoradio-therapy group(CRT group)and observation group(O group).χ2 test was used to compare the clinical baseline data and pathological information of the three groups of patients.The Kaplan-Meier survival curve and log-rank test were used to compare the disease free survival(DFS)and recurrence free survival(RFS)of the three groups of patients,and the Cox proportional hazards regression model was used on DFS and RFS by univariate and multivariate analysis.Results·Among all 67 patients,there were 23 cases in the S group,19 cases in the CRT group,and 25 cases in the O group.There was no significant difference in age(P=0.080),gender(P=0.078),tumor length(P=0.485),tumor location(P=0.655),lesion circumferential ratio(P= 0.310),histological grading(P=0.084),depth of tumor invasion(P=0.066)and lymphovascular invasion(P=0.279)among the three groups.During(42.6±16.7)months of follow-up,tumor recurrence was observed in 10 cases(14.9%),including 6 patients(60%)with local recurrence,2 patients(20%)with regional lymph recurrence and 2 patients(20%)with distant metastasis.The median recurrence time of group S,group CRT,and group O was 40.1,36.6,and 22.1 months,and the 3-year DFSs were 100%,89.5%,and 74.5%(P-trend=0.040).Multivariate Cox analysis showed that additional esophagectomy was the key to improving independent protective factors of RFS(HR=0.097,95%CI 0.010?0.956,P=0.046).Conclusion·For patients with superficial esophageal squamous cell carcinoma confirmed as pT1b after ESD,additional surgery can significantly reduce the possibility of long-term recurrence.
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Objective To explore the application value of CT texture analysis for evaluating Ki-67 expression in patient with esophageal squamous cell carcinoma.Methods Sixty-one cases of pathologically confirmed esophageal squamous cell carcinoma patients were selected to obtain the Ki-67 protein expression status of the patients'pathological tissues,and the patients were divided into a high-expression group and a low-expression group.All patients underwent plain and enhanced chest CT within two weeks before surgery.Lesions delineation and texture feature extraction of esophageal cancer were obtained via Omni-Kinetics software.The texture parameters included Min Intensity,Max Intensity,Median Intensity,Mean Intensity,Deviation,Skewness,Kurtosis,Entropy,Energy,Correlation,Haralick,short run high grey level emphasis(SRHGLE),short run low grey level emphasis(SRLGLE),long run high grey level emphasis(LRHGLE),long run low grey level emphasis(LRLGLE),Grey Level Nonuniformity,Run Length Nonuniformity.The differences of texture features among different Ki-67 expression groups were compared,and the receiver operating characteristic(ROC)curve was used to analyze the predictive value of Ki-67 expression in patient with esophageal cancer.Results In plain CT images,the SRHGLE and Grey Level Nonuniformity of the high expression group were significantly higher than those of the low expression group(P=0.010,0.002,respectively).In enhanced CT images,the Mean Intensity,Entropy and Grey Level Nonuniformity of the high expression group were significantly higher than those of the low expression group(P=0.026,0.037,0.001,respectively),and SRHGLE and LRHGLE of the high expression group were significantly lower than those of the low expression group(P=0.016,0.010,respectively).The area under the curve(AUC)of texture features in plain CT were 0.676-0.740,and the AUC of combined diagnosis reached 0.770[95%confidence interval(CI):0.645,0.868],and sensitivity and specificity was 0.921,0.565,respectively.In enhanced CT,the AUC of texture features were 0.629-0.750,the AUC of combined diagnosis increased to 0.903(95%CI:0.799,0.964),and sensitivity and specificity was 0.816,0.826,respectively.Conclusion CT texture analysis can early and non-invasively predict Ki-67 expression in patient with esophageal squamous cell carcinoma,it can be used as an imaging marker to evaluate the proliferative activity of esophageal cancer cells,and may provide diagnosis and treatment information for clinical decision-making of esophageal squamous cell carcinoma.
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Objective This study aimed to explore the prognostic value of 18F-FDG PET/CT Metabolic and Heterogeneity Parameters Combined with Clinical Features Before Definitive Chemoradiotherapy(D-CRT)in predicting the prognosis of esophageal squamous cell carcinoma(ESCC)Patients.Methods A retrospective analysis was conducted on clinical data from 106 patients with ESCC who received D-CRT at the first affiliated Hospital of University of Science and Technology of China between January 2017 and December 2021.All patients underwent 18F-FDG PET/CT examination before the treatment.The primary tumor′s metabolic and heterogeneity parameters were obtained through data processing.All patients were followed up for overall survival.The Kaplan-Meier method and Cox proportional hazards models were used to analyze the association between clinical features,tumor metabo-lism and heterogeneity parameters and patient prognosis.Results The 1-and 1.5-year overall survival rates of all patients were 77.4%and 51.9%.The median survival time was 20 months.Univariate analysis showed that N stage,M stage,metabolic tumor volume,total lesion glycolysis,heterogeneity index-2(HI-2),and coefficient of variation with a threshold of 40%maximum standard uptake value(CV40%)were correlated with the prognosis of ESCC(all P<0.05).Multivariate analysis showed that N stage and CV40%were independent predictors of prognosis in patients with ESCC(P = 0.039 and P<0.001,respectively).Conclusion N stage and tumor metabolic heterogeneity parameter CV40%,which offering a degree of predictive value,are closely related to the prognosis of patients with ESCC treated with D-CRT.
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Objective:To summarize and analyze the clinical outcome of minimally invasive McKeown esophagectomy for esophageal squamous cell carcinoma.Methods:We retrospectively analyzed the clinical data of patients with esophageal squamous cell carcinoma who received minimally invasive McKeown esophagectomy in Peking Union Medical College Hospital from January 2017 to December 2022. Improved anesthesia methods, monitoring of recurrent laryngeal nerve, minimally invasive gastrostomy, and jejunostomy techniques were introduced in surgical procedure. We evaluated perioperative data and long-term follow-up survival in these patients.Results:A total of 226 esophageal squamous cell carcinoma patients who met the inclusion and exclusion criteria were enrolled, of which 48.2% received neoadjuvant therapy. The mean operation time was( 327 ± 68) min, with a total of 40.5(33, 50) lymph nodes and 27(19, 33) thoracic lymph nodes harvested. The postoperative hospital stay was 9(7, 12) days, and the postoperative complication rate was 36.3%. In terms of learning curve, after 50 patients intraoperative blood loss, postoperative hospital stay, and recurrent laryngeal nerve injury rate were significantly decreased. The number of total lymph nodes, thoracic lymph nodes, and the 106tbl harvested was significantly increased. The median follow-up time was 23.5(14, 47) months, with a loss of follow-up rate of 3.5%. The overall 2-year and 5-year survival rates were 82.6% and 71.8%, respectively.Conclusion:Improved minimally invasive McKeown esophagectomy for esophageal squamous cell carcinoma are safe and acceptable. Learning curve can be shortened, with increased lymph node harvested and decreased postoperative complications, which improving the short-term and long-term outcomes of patients.
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@#Objective To explore the safety of minimally invasive esophagectomy (MIE) with three-field lymphadenectomy (3-FL) for esophageal squamous cell carcinoma (ESCC) by comparing the short-term outcomes between the 3-FL and the two-field lymphadenectomy (2-FL) in MIE. Methods The clinical data of patients with ESCC who underwent minimally invasive McKeown esophagectomy in our hospital from July 2015 to March 2022 were collected retrospectively. Patients were divided into a 3-FL group and a 2-FL group according to lymph node dissection method. And the clinical outcomes and postoperative complications were compared between the two groups. Results A total of 257 patients with ESCC were included in this study. There were 211 males and 46 females with an average age of 62.2±8.1 years. There were 109 patients in the 3-FL group and 148 patients in the 2-FL group. The operation time of the 3-FL group was about 20 minutes longer than that of the 2-FL group (P<0.001). There was no statistical difference between the two groups in the intraoperatve blood loss (P=0.376). More lymph nodes (P<0.001) and also more positive lymph nodes (P=0.003) were obtained in the 3-FL group than in the 2-FL group, and there was a statistical difference in the pathological N stage between the two groups (P<0.001). But there was no statistical difference in the incidence of anastomotic leak (P=0.667), chyle leak (P=0.421), recurrent laryngeal nerve injury (P=0.081), pulmonary complications (P=0.601), pneumonia (P=0.061), cardiac complications (P=0.383), overall complications (P=0.147) or Clavien-Dindo grading (P=0.152) between the two groups. Conclusion MIE 3-FL can improve the efficiency of lymph node dissection and the accuracy of tumor lymph node staging, but it does not increase the postoperative complications, which is worthy of clinical application.
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@#Objective To investigate the prognostic value of preoperative serum albumin-to-globulin ratio (AGR) and neutrophil-lymphocyte ratio (NLR) in the overall survival (OS) of patients with esophageal squamous cell carcinoma (ESCC), and to establish an individualized nomogram model and evaluate its efficacy, in order to provide a possible evaluation basis for the clinical treatment and postoperative follow-up of ESCC patients. Methods AGR, NLR, clinicopathological and follow-up data of ESCC patients diagnosed via pathology in the Department of Thoracic Surgery, The First Affiliated Hospital of Xinjiang Medical University from 2010 to 2017 were collected. The correlation between NLR/AGR and clinicopathological data were analyzed. Kaplan-Meier analysis and log-rank test were used for survival analysis. The optimal cut-off values of AGR and NLR were determined by X-tile software, and the patients were accordingly divided into a high-level group and a low-level group. At the same time, univariate and multivariate Cox regression analyses were used to identify independent risk factors affecting OS in the ESCC patients, and a nomogram prediction model was constructed and internally verified. The diagnostic efficacy of the model was evaluated by receiver operating characteristic (ROC) curve and calibration curve, and the clinical application value was evaluated by decision curve analysis. Results A total of 150 patients were included in this study, including 105 males and 45 females with a mean age of 62.3±9.3 years, and the follow-up time was 1-5 years. The 5-year OS rate of patients in the high-level AGR group was significantly higher than that in the low-level group (χ2=6.339, P=0.012), and the median OS of the two groups was 25 months and 12.5 months, respectively. The 5-year OS rate of patients in the high-level NLR group was significantly lower than that in the low-level NLR group (χ2=5.603, P=0.018), and the median OS of the two groups was 18 months and 39 months, respectively. Multivariate Cox analysis showed that AGR, NLR, T stage, lymph node metastasis, N stage, and differentiation were independent risk factors for the OS of ESCC patients. The C-index of the nomogram model was 0.689 [95%CI (0.640, 0.740)] after internal validation. The area under the ROC curve of predicting 1-, 3-, and 5-year OS rate was 0.773, 0.724 and 0.725, respectively. At the same time, the calibration curve and the decision curve suggest that the model had certain efficacy in predicting survival and prognosis. Conclusion Preoperative AGR and NLR are independent risk factors for ESCC patients. High level of AGR and low level of NLR may be associated with longer OS in the patients; the nomogram model based on AGR, NLR and clinicopathological features may be used as a method to predict the survival and prognosis of ESCC patients, which is expected to provide a reference for the development of personalized treatment for patients.
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Objective:To explore the effect of complement component C1s on the proliferation,migration and adhesion of esophageal squamous cell carcinoma(ESCC)cells and on the growth of xenograft tumors in nude mice.Methods:The C1S mRNA ex-pression of ESCC tissues and adjacent normal tissues(ANTs)were analyzed using NCBI-GEO database.The C1s expression of ESCC cell lines was analyzed with RT-qPCR and Western blot.The knockdown or overexpression of C1s in ESCC cells lines was performed using C1s small interfering RNA(siRNA),C1s short hairpin RNA(shRNA)or C1s overexpression lentivirus,and the cell prolifera-tion was detected by CCK-8 assay,cell migration was detected by cell wound healing assay,cell adhesion was detected by cell-matrix adhesion assay,the expressions of matrix metalloproteinases MMP1 and MMP13 were detected by Western blot,and the effect of C1s on the growth of xenograft tumors in nude mice was detected by subcutaneous tumorigenesis assay in nude mice.The expression of CD34 in the xenograft tumors was detected by immunohistochemistry,and the formation of tumor microvessel was analyzed.Results:The expression of C1S mRNA in ESCC tissues was significantly higher than that in ANTs.Knockdown of C1s significantly suppressed proliferation,migration and cell-matrix adhesion of ESCC cells,as well as growth of xenograft tumors in nude mice,while overexpres-sion of C1s had the opposite effects.The expressions of MMP1 and MMP13 were decreased in ESCC cells TE-1 with C1s knockdown.Compared with control group,the microvessel of the xenograft tumors in the C1s overexpression group were more abundant.Conclu-sion:C1s is significantly upregulated in ESCC tissues,and promotes proliferation,migration,cell-matrix adhesion of ESCC cells,and the growth of xenograft tumors.C1s may play an important role in the occurrence and development of ESCC.
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Objective:To compare the efficacy and safety of adjuvant radiotherapy versus surgery alone in patients with stage pT 2-3N 0M 0 esophageal squamous cell carcinoma after radical resection. Methods:The search was conducted through Web of Science, Emabse, PubMed, Cochrane Library, CNKI, Chongqing VIP, China Biomedical Literature Database, and Wanfang database, etc. The search time was ranged from the establishment of the database to December 2022. Searched studies were screened according to the inclusion and exclusion criteria. Review Manager 5.4 software was used for analysis.Results:Clinical data of 2 424 patients from 8 controlled clinical studies were finally included. Meta-analysis showed that postoperative adjuvant radiotherapy had higher 3-year and 5-year disease-free survival rates ( OR=2.33, 95%CI=1.71-3.17, P<0.001; OR=2.38, 95% CI=1.73-3.27, P<0.001) and 3-year and 5-year overall survival rates ( OR=1.89, 95% CI=1.37-2.60, P<0.01; OR=1.94,95% CI=1.50-2.49, P<0.001) than surgery alone. Meanwhile, the local recurrence rate ( OR=0.33, 95% CI=0.21-0.50, P<0.001) and distant metastasis rate ( OR=0.62, 95% CI=0.39-0.98, P=0.040) of postoperative adjuvant radiotherapy group were lower than those in the surgery alone group. The incidence of radiation esophagitis (1.4%-9.5%), radiation pneumonitis (2.1%) and anastomotic stenosis (5.3%) was reported. Conclusions:For patients with stage pT 2-3N 0M 0 squamous cell carcinoma after radical resection of esophageal cancer, adjuvant radiotherapy may improve 3-year and 5-year disease-free survival rates and 3-year and 5-year overall survival rates compared with surgery alone. In addition, adjuvant radiotherapy may reduce the local recurrence and distant metastasis rates. Therefore, postoperative adjuvant radiotherapy is an optional treatment for stage pT 2-3N 0M 0 esophageal squamous cell carcinoma.
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Objective:To evaluate the long-term efficacy of radiotherapy for elderly patients with esophageal squamous cell carcinoma.Methods:Clinical data of 118 elderly patients aged ≥65 years with esophageal squamous cell carcinoma treated with radiotherapy alone or concurrent chemoradiotherapy in Cancer Hospital affiliated to Xinjiang Medical University from January 2013 to January 2016 were retrospectively analyzed. All patients were randomly divided into the radiotherapy alone ( n=57) and concurrent chemoradiotherapy groups ( n=61). The effective rate, survival rate, adverse reactions and causes of death were compared between two groups. Rate and constituent ratio were used to describe the categorical variables, and Pearson Chi-square test was used for univariate analysis. Results:The effective rate (68.4% vs. 86.9%, P=0.016) and incidence of adverse reactions (21.1% vs. 50.9%, P<0.001) between radiotherapy alone and concurrent chemoradiotherapy groups were significantly differed. The 1-year overall survival rate significantly differed between two groups (75.4% vs. 91.8%, P=0.016), while no significant differences were observed in the 3-year overall survival rate (36.8% vs. 42.7%, P=0.088) and 5-year overall survival rate (10.7% vs. 18.0%, P=0.746). The main cause of death in two groups was recurrence combined with distant metastasis. Conclusion:Compared with the radiotherapy alone, concurrent chemoradiotherapy can significantly improve the effective rate and survival rate for elderly patients with esophageal squamous cell carcinoma, whereas it may increase the incidence of adverse reactions.
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SUMMARY: This study is to investigate the effect of survivin down-regulation by Egr1-survivin shRNA combined with radiotherapy on the apoptosis and radiosensitivity of esophageal squamous cell carcinoma ECA109 and KYSE150 cells. ECA109 and KYSE150 cells were transfected with Egr1-survivin shRNA, and then treated with radiotherapy. After 24 h, the mRNA and protein levels of Egr1-survivin were detected by qPCR and Western-Blot. Cell cycle and apoptosis were detected by flow cytometry. Western blot also detected levels of cleavaged Caspase 3 and Caspase 9. YM155 was used as a positive control to inhibit survivin expression. The levels of survivin mRNA and protein in ECA109 and KYSE150 cells treated with Egr1-survivin shRNA combined with radiotherapy were significantly lower than those of the blank control group, the empty vector control group, and, the YM155 + radiotherapy group (P<0.05). Meanwhile, after survivin down-regulation, the ratio of G2 to S phase of ECA109 and KYSE150 cells increased significantly, leading to significant G2 and S phase arrest. Additionally, apoptosis of ECA109 and KYSE150 cells increased significantly (P <0.01). Further, protein levels of cleavaged Caspase 3 and Caspase 9 significantly increased in Egr1-survivin shRNA combined with radiotherapy group. Egr1-survivin shRNA combined with radiotherapy can down-regulate survivin expression, which further increases the apoptosis, and enhances the radiosensitivity of ECA109 and KYSE150 cells.
Este estudio tuvo como objetivo investigar el efecto de la regulación negativa de survivina por el shRNA de Egr1-survivina combinado con radioterapia sobre la apoptosis y la radiosensibilidad del carcinoma de células escamosas de esófago Células ECA109 y KYSE150. Las células ECA109 y KYSE150 se transfectaron con shRNA de survivina Egr1 y luego se trataron con radioterapia. Después de 24 h, los niveles de ARNm y proteína de Egr1-survivina se detectaron mediante qPCR y Western-Blot. El ciclo celular y la apoptosis se detectaron mediante citometría de flujo. La transferencia Western también detectó niveles de Caspasa 3 y Caspasa 9 escindidas. Se usó YM155 como control positivo para inhibir la expresión de survivina. Los niveles de ARNm y proteína de survivina en células ECA109 y KYSE150 tratadas con shRNA de survivina Egr1 combinado con radioterapia fueron significativamente más bajos que los del grupo control en blanco, el grupo control de vector vacío y el grupo de radioterapia YM155 + (P <0,05). Mientras tanto, después de la regulación negativa de survivina, la proporción entre las fases G2 y S de las células ECA109 y KYSE150 aumentó significativamente, lo que llevó a una detención significativa de las fases G2 y S. Además, la apoptosis de las células ECA109 y KYSE150 aumentó significativamente (P <0,01). Además, los niveles de proteína de Caspasa 3 y Caspasa 9 escindidas aumentaron significativamente en el shRNA de Egr1- survivina combinado con el grupo de radioterapia. El shRNA de survivina de Egr1 combinado con radioterapia puede regular negativamente la expresión de survivina, lo que aumenta aún más la apoptosis y mejora la radiosensibilidad de las células ECA109 y KYSE150.
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Humanos , Neoplasias Esofágicas/terapia , Survivina , Carcinoma de Células Escamosas do Esôfago/terapia , Radiossensibilizantes , Tolerância a Radiação , RNA Mensageiro , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Transfecção , Regulação para Baixo , Western Blotting , Apoptose , Terapia Combinada , RNA Interferente Pequeno , Linhagem Celular Tumoral/efeitos da radiação , Proteína 1 de Resposta de Crescimento Precoce , Caspase 3 , Caspase 9 , Reação em Cadeia da Polimerase em Tempo Real , Citometria de Fluxo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/radioterapiaRESUMO
OBJECTIVE To evaluate the cost-effectiveness of serplulimab combined with chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma from the perspective of the Chinese healthcare system. METHODS A partitioned survival model with three health states was constructed for cost-effectiveness analysis. Clinical data were extracted from ASTRUM- 007. Information on parameters such as cost and health utility was derived from related websites and published literature. The quality-adjusted life years （QALYs） was used as the output index to calculate the incremental cost-effectiveness ratio （ICER）， and then compared with three times the per capita gross domestic product （GDP） in China to judge whether it was cost-effective. One- way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the robustness of the model； the cost- effectiveness of applying this plan to subgroup patients with programmed cell death-ligand 1 combined positive score （PD-L1 CPS） ≥10 and the scheme in the context of charitable drug donations was explored. RESULTS Among advanced or metastatic oesophageal squamous cell carcinoma patients and patients with PD-L1 CPS ≥10， serplulimab combined with chemotherapy could improve health outcomes with an augmentation of cost， compared with placebo combined with chemotherapy，resulting the ICERs were 599 623.64 yuan/QALY and 629 121.57 yuan/QALY， respectively. Therefore， serplulimab combined with chemotherapy was not cost-effective. Sensitivity analysis of single factor showed that the costs of serplulimab were the crucial factor affecting the ICER； probabilistic sensitivity analysis demonstrated basic analysis results were relatively robust. The results of scenario analysis showed that when all patients met the requirements of the charitable drug donation program， serplulimab combined with chemotherapy was cost-effective； the economic outcome of this scheme was reversed compared with the results of the basic analysis. CONCLUSIONS From Chinese healthcare perspective， first-line treatment with serplulimab in combination with chemotherapy is not a cost-effective option for patients with advanced esophageal squamous cell carcinoma， but it may be an economic option to implement a charitable drug donation program for all patients or if the price of serplulimab is significantly reduced.
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Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.
Assuntos
Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Cisplatino/metabolismo , Neoplasias Esofágicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Escamosas/genética , Fator 15 de Diferenciação de Crescimento/uso terapêutico , Receptor do Fator de Crescimento Transformador beta Tipo II/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão GênicaRESUMO
Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
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Objective To investigate the role and mechanism of the small-molecule inhibitor CIL56 in the death of esophageal squamous cell carcinoma cells. Methods SRB method and plate-cloning method were used to detect the effect of CIL56 on the proliferation of esophageal squamous cell carcinoma. The effect of CIL56 on the migration of esophageal squamous cell carcinoma cells was investigated by scratch-healing test. The effect of CIL56 on the concentration of iron ions in esophageal squamous cell carcinoma was detected with an iron-detection kit. A total glutathione test kit was used to examine the effect of CIL56 on glutathione concentration in esophageal squamous cell carcinoma. Western blot was used to investigate the effect of CIL56 on the expression of xCT and GPX4 proteins related to iron death, as well as YAP1 protein, in esophageal squamous cell carcinoma. Results CIL56 could significantly inhibit the proliferation (P < 0.05) and migration (P < 0.001) of esophageal squamous cell carcinoma. With the increased CIL56 concentration, the iron concentration in esophageal squamous cell carcinoma increased (P < 0.05). CIL56 could reduce the glutathione content in esophageal squamous cell carcinoma (P < 0.01). CIL56 could reduce the expression of xCT and GPX4 proteins related to iron death and decrease the level of YAP1 protein in esophageal squamous cell carcinoma (both P < 0.001). Conclusion The small-molecule inhibitor CIL56 can significantly inhibit the proliferation and migration of esophageal squamous cell carcinoma cells and reduce the expression of the iron-death-related proteins xCT and GPX4, as well as YAP1 protein.
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Objective To investigate the role of lncRNA PTENP1 in regulating TGF-β-induced epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC). Methods Eca109 and TE-1 cells were treated with TGF-β1, and the expression of PTENP1 was detected by qRT-PCR before and after treatment. PTENP1-overexpressing stably transfected cell lines were constructed in Eca109 and TE-1 cells. The effects of overexpression of PTENP1 on TGF-β1-induced migration, proliferation and EMT-related proteins expression in Eca109 and TE-1 cells were detected by Transwell assay, CCK-8 test and Western blot, respectively. Results The expression of PTENP1 was significantly decreased in Eca109 and TE-1 cells treated with TGF-β1 (P < 0.05). Overexpression of PTENP1 significantly prevented cell migration, decreased the cell vitality, upregulated the E-cadherin expression, and downregulated the expression of N-cadherin and vimentin in Eca109 and TE-1 cells (P < 0.05). Furthermore, PTENP1 overexpression attenuated TGF-β-induced migration of Eca109 and TE-1 cells. PTENP1 overexpression partially reversed TGF-β-induced EMT (P < 0.05). Conclusion PTENP1 plays an important role in TGF-β-induced EMT in ESCC cells.
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Objective To investigate the difference in intestinal flora among patients with esophageal squamous cell carcinoma and normal population and to provide a basis for the early diagnosis of esophageal squamous cell carcinoma as a marker. Methods DNA was extracted from biopsy tissue samples of 30 patients with esophageal squamous cell carcinoma (observation group) and 25 healthy people (control group) by microbial amplification sequencing. The integrity and quality of DNA were detected. The composition and abundance of intestinal flora in the samples of the two groups were determined. Results A great similarity in beta diversity was found between the two groups, but some differences were also observed. The relative abundance of Proteobacteria and Verrucomicrobia in the observation group was higher than that in the control group (P<0.05). The relative abundance of Megamonas in the observation group was lower than that in the control group (P=0.025). Conclusion Strengthening the study on the changes in intestinal flora among patients with esophageal squamous cell carcinoma may be of great significance for its prevention and treatment.