ObjectiveTo explore the effects and molecular mechanisms of histone methylase G9a inhibitor BIX-01294 on apoptosis in esophageal squamous cell carcinoma (ESCC).MethodsMTT assay and Colony-forming Units were adopted to determine the effects of BIX-01294 on the growth and proliferation of ESCC cell lines EC109 and KYSE150. Flow cytometry was used to analyze the apoptosis status of ESCC cells after the treatment of BIX-01294. The effects of BIX-01294 treatment on the expressions of G9a catalytic product H3K9me2, DNA double-strand break (DSB) markers, and apoptosis-related proteins were detected by Western blotting.ResultsBIX-01294 inhibited the growth of EC109 and KYSE150 cells in a dose-dependent manner (P<0.05), and BIX-01294 with the inhibitory concentration 50% (IC50) significantly inhibited the formation of colony (P<0.05). After 24 hours treatment of BIX-01294 (IC50), the apoptosis rate of EC109 cells increased from 11.5%±2.1% to 42.5%±5.4%, and KYSE150 cells from 7.5%±0.9% to 49.2%±5.2% (P<0.05). The expression level of the G9a catalytic product, H3K9me2, significantly decreased (P<0.05); while the expression of the DSB marker γH2AX was dramatically enhanced (P<0.05). We also found that the mitochondrial apoptosis pathway was activated and the expression levels of cleaved caspase3 and cleaved PARP were significantly elevated (P<0.05).ConclusionBIX-01294, the inhibitor of methyltransferase G9a, prompted apoptosis in ESCC cells by inducing DSB damage and activating mitochondrial apoptosis pathway.
Increasing evidence suggests that many types of cancers contain a population of cells that display stem cell properties. These cells are called cancer stem cells （CSCs），which are closely related to tumor initiation，growth，metastasis and chemoresistance. CSCs are also found in esophageal squamous cell carcinoma （ESCC）. These cells are characterized by potential of self-renewal and differentiation，tumor formation in nude mice and chemotherapy resistance，and thus may play an important role in targeted cancer therapies. Current methods for culturing and sorting CSCs in ESCC mainly include fluorescence activated cell sorting （FACS），magnetic activated cell sorting （MACS），suspension culture，and side population （SP） cell sorting. In this review，we focus on current research methods for CSCs in ESCC，their biological characteristics and areas for improvement. We believe that a combination of multiple cell-surface makers is needed for research of CSCs in ESCC.
ObjectiveTo 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. MethodsAGR, 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. ResultsA 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. ConclusionPreoperative 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.
Objective To summarize the progress and trend on clinical drug trials of esophageal squamous cell carcinoma in China. Methods Based on the clinical drug trial registration and information disclosure platform and the drug data query system of the National Medical Products Administration, the characteristics of clinical trials, investigational drugs and listed drugs of esophageal squamous cell carcinoma in China from 2012 to 2021 were analyzed. Results From 2012 to 2021, a total of 49 clinical drug trials of esophageal squamous cell carcinoma were registered in China, accounting for 1.6% of all clinical trials of anticancer drugs. Among them, there were 39 (79.6%) trials initiated by domestic pharmaceutical enterprises, 6 (12.2%) for adjuvant and neoadjuvant treatment, and 9 (18.4%) for local treatment. There were differences in the treatment line distribution between global and domestic enterprise-initiated trials (P=0.032). The above trials covered 29 investigational drugs, including 23 (79.3%) targeted drugs, most of which targeted programmed death-1, programmed death-ligand 1 and epidermal growth factor receptor. From 2012 to 2021, there were 2 drugs for esophageal squamous cell carcinoma listed in China, both of which were approved for the first-line and second- line treatment. Conclusion Great achievements have been made in the clinical development of esophageal squamous cell carcinoma drugs in China. It is suggested that domestic enterprises increase the investment of esophageal squamous cell carcinoma, pay attention to adjuvant and local treatment, explore novel targets and drug categories, and focus on the details of pivotal trials.
Objective To observe the growth of xenografted tumor in nude mice after DDX46 expression decreased, and to further study the role of DDX46 in the development and progression of esophageal squamous cell carcinoma. Methods DDX46-shRNA mediated RNAi was applied to silencing DDX46 in Eca-109 cells. Twenty-five female BALB/c nude mice were divided into 3 groups: an experiment group (DDX46-shRNA-LV, n=10), a control group (Control-LV, n=10) and a blank control group (Het-1A, n=5). The prepared Eca-109 cells of DDX46-shRNA-LV and Control-LV were subcutaneously injected into the right armpit of mice (4×106 cells per mouse), while Het-1A cells were subcutaneously injected into the bilateral armpits of mice (4×106 cells per side). Tumor growth was monitored twice a week on the 14th day after injection. Tumor volume was measured with calipers, in vivo imager to observe the fluorescence of each group. Further, western blotting analysis was used to detect the changes of apoptosis signaling molecules in xenografted tumor after DDX46 silence. Results The growth of xenografted tumor in nude mice was significantly slower in the DDX46-shRNA-LV group than that in the Control-LV group throughout the study period (P<0.001). Western blotting analysis showed that silencing DDX46 effectively suppressed the expression of DDX46, and upregulated the expression of cleaved Caspase-3 and cleaved PARP-1 in xenografted tumor (P<0.01). Conclusion DDX46 is involved in the development and progression of esophageal squamous cell carcinoma, and the silence of DDX46 expression can inhibit the growth of esophageal squamous cell carcinoma, which probably by positive regulation of apoptosis signaling pathway.
ObjectiveTo compare the short-term and long-term effects of minimally invasive esophagectomy (MIE) and traditional open esophagectomy (OE) in patients with stage T1b esophageal squamous cell carcinoma (ESCC).MethodsWe retrospectively analyzed the clinical pathology data of 162 patients undergoing thoracic surgery at Northern Jiangsu People's Hospital from 2015 to 2018 whose pathological diagnosis was stage pT1b ESCC. According to the surgical approach, they were divided into MIE group and OE group. There were 55 males and 21 females in the OE group, with an average age of 63.3±5.6 years, and 60 males and 26 females in the MIE group, with an average age of 64.7±6.1 years. The preoperative, intraoperative and postoperative data of the two groups were compared and followed up. Survival data were compared using Kaplan-Meier and log-rank tests between the two groups, and Cox proportional hazard regression models were used to analyze prognostic factors.ResultsCompared with the OE group, the intraoperative bleeding volume of the MIE group was less (119.8±70.0 mL vs. 210.5±136.2 mL, P<0.001), and the lymph nodes dissected during the operation were more (19.1±7.4 vs. 13.8±5.9, P<0.001), the rate of postoperative pulmonary infections was lower (9.3% vs. 21.1%, P=0.036), but the operation time was longer (240.0±52.4 min vs. 179.5±35.7 min, P<0.001). Twenty-one patients had lymph node metastasis, and the lymph node metastasis rate was 13.0%. At the end of the follow-up, 19 patients died, and the overall survival (OS) at 1 year, 3 years, and 5 years after operation were 97.5%, 88.8% and 82.9%, respectively; 31 patients had recurrence and metastasis, and the disease-free survival (DFS) rate at 1 year, 3 years, and 5 years after operation was 95.1%, 80.9% and 75.6%. There was no significant difference in OS and DFS between the two groups. Multivariate Cox regression analysis of OS found that lymph node metastasis, anastomotic fistula and chylothorax were independent risk factors for OS. Multivariate Cox regression analysis of DFS found that lymph node metastasis, anastomotic fistula, chylothorax, and vascular cancer thrombus were independent risk factors for OS.ConclusionMIE can achieve the same long-term effects as OE, with less intraoperative bleeding, more lymph nodes dissected, and lower incidence of postoperative pulmonary infections, but it takes longer operation time.
ObjectiveTo investigate the prognostic factors of primary gastric squamous cell carcinoma (SCC) and develop a nomogram for predicting the survival of gastric SCC.MethodsData of 199 cases of primary gastric SCC from 2004 to 2015 were collected in the National Cancer Institute SEER database by SEER Stat 8.3.5 software. X-tile software was used to determine the best cut-off value of the age, SPSS 25.0 software was used to analyze the prognostic factors of gastric SCC and draw a Kaplan-Meier curve, and then the Cox proportional hazard regression model analysis was performed to obtain independent prognostic factors of gastric SCC. We used R studio software to visualize the model and draw a nomogram. C-index was used to evaluate the prediction effect of the nomogram. Bootstrap analyses with 1 000 resamples were applied to complete the internal verification of the nomogram.ResultsAmong the 199 patients, survival rates for 1-, 3-, and 5-year were 40.7%, 22.4%, and 15.4%, respectively. Age (χ2=6.886, P=0.009), primary site (χ2=14.918, P=0.037), race (χ2=7.668, P=0.022), surgery (χ2=16.523, P<0.001), histologic type (χ2=9.372, P=0.009), T stage (χ2=11.639, P=0.009), and M stage (χ2=31.091, P<0.001) had a significant correlation with survival time of patients. The results of the Cox proportional hazard regression model showed that, age [HR=1.831, 95%CI was (1.289, 2.601)], primary site [HR=1.105, 95%CI was (1.019, 1.199)], M stage [HR=2.222, 95%CI was (1.552, 3.179)], and surgery [HR=0.561, 95%CI was (0.377, 0.835)] were independent prognostic factors affecting the survival of gastric SCC. Four independent prognostic factors contributed to constructing a nomogram with a C-index of 0.700.ConclusionIn this research, a reliable predictive model is constructed and drawn into a nomogram, which can be used for clinical reference.
Esophageal cancer is a serious threat to the health of Chinese people. The key to solve this problem is early diagnosis and early treatment, and the most important method is endoscopic screening. The rapid development of artificial intelligence (AI) technology makes its application and research in the field of digestive endoscopy growing, and it is expected to become the "right-hand man" for endoscopists in the early diagnosis of esophageal cancer. Currently, the application of multimodal and multifunctional AI systems has achieved good performance in the diagnosis of superficial esophageal squamous cell carcinoma and precancerous lesions. This study summarized and reviewed the research progress of AI in the diagnosis of superficial esophageal squamous cell carcinoma and precancerous lesions, and also explored its development direction in the future.
Objective To evaluate the security and outcomes of thoracolaparoscopic esophagectomy (TLE) versus open approach (OA) for thoracic esophageal squamous cell carcinoma. Methods From June 2014 to June 2015, 125 patients with thoracic esophageal squamous cell carcinoma underwent esophagectomy through McKeown approach, including TLE (a TLE group, 107 patients, 77 males and 30 females) and OA (an OA group, 18 patients, 13 males and 5 females). The data of operation and postoperative complications of the two groups were analyzed retrospectively. Results There was no statistical difference in the duration of operation and ICU stay and resected lymph nodes around laryngeal recurrent nerve between the TLE group and the OA group (333.58±72.84 min vs. 369.17±91.24 min, P=0.067; 2.84±1.44 d vs. 6.44±13.46 d, P=0.272; 4.71±3.87 vs. 3.89±3.97, P=0.408) . There was a statistical difference in blood loss, total resected lymph nodes and resected lymph nodes groups between TLE group and OA group (222.62±139.77 ml vs. 427.78±276.65, P=0.006; 19.62±9.61 vs. 14.61±8.07, P=0.038; 3.70±0.99 vs. 3.11±1.13, P=0.024). The rate of postoperative complications was 32.7% in the TLE group and 38.9% in the OA group (P=0.608). There was a statistical difference (P=0.011) in incidence of pulmonary infection (2.8% in the TLE group and 16.7% in the OA group). Incidences of complications, such as anastomotic leakage, cardiac complications, left-side hydrothorax, right-side pneumothorax, voice hoarse and incision infection, showed no statistical difference between two groups. Conclusion For patients with thoracic esophageal squamous cell carcinoma, TLE possesses advantages of more harvested lymph nodes, less blood loss and less pulmonary infection comparing with open approach, and is complied with the principles of security and oncological radicality of surgery.
ObjectiveTo explore the effect of DDX46 silencing on growth and apoptosis in esophageal squamous cell carcinoma cell TE-1 by the shRNA. MethodsThe relative expression of DDX46 mRNA in TE-1 cells was detected by real-time quantitative polymerase chain reaction (qRT-PCR) and compared with immortalized human esophageal squamous cell Het-1A. DDX46 shRNA-expressing lentivirus was applied to silence DDX46 (experimental group), and non-silencing control lentivirus was added (control group) with a multiplicity of infection of 5 in TE-1 cells. In both groups, cell growth was monitored using high content screening, cell colony-forming capacity was measured by colony formation assay, cell apoptosis were determined by flow cytometry. Further, the Stress and Apoptosis Signaling Antibody Array Kit was used to detect the changes of signaling molecules in TE-1 cells after DDX46 knockdown. ResultsCompared with the control group, cell counting after DDX46 silencing showed that TE-1 cell growth was significantly inhibited (P<0.001). Colony formation assay showed that cell colony-forming capacity was significantly inhibited (P<0.01). Annexin V-APC flow cytometry showed a significant increase in apoptosis (P<0.001). In PathScan® Antibody Array, the expression levels of Akt (Ser473, phosphorylation) and IκBα (Total, N/A) significantly decreased (P<0.01), and the expression of Caspase-3 (Asp175, cleaved) increased (P<0.05). ConclusionDDX46 is overexpressed in TE-1 cells. Targeted gene silencing of DDX46 inhibits cell growth, and induces cell apoptosis. DDX46 silencing probably by negative regulation of Akt/NF-κB signaling pathway, to play a role in inhibiting TE-1 cells growth and inducing apoptosis.