SOX2 mediates cisplatin resistance in small-cell lung cancer with downregulated expression of hsa-miR-340-5p.

BACKGROUND: This study is aimed to unravel the genetic factors associated with microRNA (miRNA) expression in regulating sex-determining region Y-box 2 (SOX2)-mediated cisplatin resistance in small-cell lung cancer (SCLC). METHODS: The relevance of SOX2 expression in SCLC was analyzed in a panel of SCLC cells by quantitative real-time PCR (qPCR) and western blot (WB). We selected DMS114 cell line, in which SOX2 was amplified via lentiviral vector-mediated transfection of the SOX2 genes and tested for the half-maximal inhibitory concentration (IC50 ) by MTS assay. High-throughput sequencing and screening of differentially expressed miRNAs between SOX2-overexpressing and normal control cells were performed. Finally, miRanda software was used to verify the miRNAs bound with SOX2 and qPCR was used to identify the expression of miRNAs which were binding with SOX2. RESULTS: Cisplatin-resistant SOX2-overexpressing DMS114 cell lines were successfully developed, showing a statistically significant increase in SOX2 expression by qPCR and WB. Our results showed a typically higher IC50 value in SOX2-overexpressing cells compared with the negative controls. The high-throughput sequencing analysis revealed that 68 miRNAs were upregulated and 24 miRNAs were downregulated in the SOX2-overexpressing cells. The 24 downregulated miRNAs were further verified. Of them, a cancer-related miRNA, hsa-miR-340-5p, showed a higher binding affinity with SOX2 in network regulation mapping, which was also found to be markedly downregulated under qPCR analysis. CONCLUSION: We demonstrated that downregulated expression of hsa-miR-340-5p may affect cisplatin resistance by mediating SOX2 expression in SCLC cells, which may provide a potential target for the therapy of chemoresistant SCLCs.

Impact of metformin on survival outcome of esophageal squamous cell carcinomas patients undergoing surgical resection: a multicenter retrospective study.

BACKGROUND: Diabetes mellitus is a recognized risk factor for esophageal squamous cell carcinomas (ESCC), and metformin is a recognized protective factor for some gastrointestinal tumors. But knowledge is limited regarding the effect of metformin on survival outcome of ESCC patients with type 2 diabetes mellitus (T2DM). We assessed the impact of post-diagnosis metformin use on overall survival (OS) and disease-free survival (DFS) in ESCC with T2DM undergoing surgical resection. METHODS: A retrospective analysis was performed on 3,523 patients with ESCC who met the study conditions after surgical resection. Log-rank and Cox regression models were used to evaluate the relationship between metformin and T2DM and ESCC survival rate, and adjusted according to age, gender, BMI, smoking, drinking and staging, et al. RESULTS: Among included ESCC patients, 619 were associated with type 2 diabetes, while the remaining 2,904 were not associated with type 2 diabetes. The 5-year OS (28.43%) of patients with T2DM was significantly lower than that of patients without T2DM (32.75%), P=0.037. DFS in 5 years were 27.30% (with T2DM) and 31.75% (without T2DM) (P=0.030), respectively. Compared with patients without T2DM, patients with T2DM presented worse OS [adjusted risk ratio (HRadj) =1.19] and DFS (HRadj =1.17; P<0.001). Among the 619 patients with type 2 diabetes, 485 were treated with metformin and 134 were not treated with metformin. Patients treated with metformin had significantly improved OS [adjusted risk ratio (HRadj) =0.89; P=0.031) and DFS (HRadj =0.90; P=0.013). CONCLUSIONS: T2DM was again associated with poorer survival in ESCC patients, and metformin may improve the prognosis of these patients.

Association between different sequences of vessel ligation during video-assisted thoracoscopic lobectomy and survival in patients with non-small cell lung cancer.

BACKGROUND: The aim of this retrospective study was to assess the influence of the sequence of pulmonary vessel ligation during video-assisted thoracoscopic lobectomy on long-term survival in patients with non-small cell lung cancer (NSCLC). METHODS: This retrospective study included 60 patients treated surgically with lobectomy and standard lymphadenectomy between 2012 and 2013. Patients had primary ligation of the pulmonary vein or veins (PV group, 33 patients) or of the pulmonary artery or arteries (PA group, 27 patients). Patients were excluded if they had undergone pulmonary wedge resection before lobectomy. Subgroup and sensitivity analyses were also used to investigate the effect of clinical characteristics of interest on survival. RESULTS: Median follow-up was 54.5 months. Baseline characteristics of the two groups were statistically comparable regarding gender, histology, type of resection, T stage, and overall stage (all P>0.05). Overall, 5-year survival reached 66.67% in the PV group and 44.44% in the PA group (P=0.084). There were no differences between two groups regarding overall survival (OS) (P=0.063, HR: 2.093; 95% CI: 0.960-4.564), disease-free survival (DFS) (P=0.180, HR: 1.539; 95% CI: 0.820-2.889), or cancer-specific deaths (P=0.227, 14/33 vs. 17/27). Subgroup analyses showed no significant difference of OS (P=0.374, HR: 1.541; 95% CI: 0.594-3.997) or DFS (PLog-rank=0.746) for isolated adenocarcinoma, but significant differences in OS (PLog-Rank=0.036; HR: 3.992; 95% CI: 0.987-16.139) and DFS (P=0.044, HR: 3.011; 95% CI: 1.031-8.795) between the two groups of patients in whom squamous cell carcinomas. Sensitivity analysis showed that the differences were not statistically significant between the two groups regarding OS (P=0.140, HR: 1.944; 95% CI: 0.804-4.700) and DFS (P=0.190, HR: 1.605; 95% CI: 0.791-3.255) for patients with a tumour diameter of greater than 3 cm. CONCLUSIONS: In summary, the sequence of pulmonary vessel ligation during video-assisted thoracoscopic lobectomy for NSCLC has no different effects on long-term survival, but for patients with squamous cell carcinoma, venous ligation should be preferred first since it may bring survival advantage after surgery.