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Background: Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. Methods: Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). Results: In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. Conclusion: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the potential prognostic value of DNA damage repair genes (DDRGs) in esophageal squamous cell carcinoma (ESCC) and their relationship with immune-related characteristics. Methods: We analyzed DDRGs of the Gene Expression Omnibus database (GSE53625). Subsequently, the GSE53625 cohort was used to construct a prognostic model based on least absolute shrinkage and selection operator regression, and Cox regression analysis was used to construct a nomogram. The immunological analysis algorithms explored the differences between the potential mechanism, tumor immune activity, and immunosuppressive genes in the high- and low-risk groups. Of the prognosis model-related DDRGs, we selected PPP2R2A for further investigation. Functional experiments were conducted to evaluate the effect on ESCC cells in vitro. Results: A 5-DDRG (ERCC5, POLK, PPP2R2A, TNP1 and ZNF350) prediction signature was established for ESCC, stratifying patients into two risk groups. Multivariate Cox regression analysis showed that the 5-DDRG signature was an independent predictor of overall survival. Immune cells such as CD4 T cells and monocytes displayed lower infiltration levels in the high-risk group. Additionally, the immune, ESTIMATE, and stromal scores in the high-risk group were all considerably higher than those in the low-risk group. Functionally, knockdown of PPP2R2A significantly suppressed cell proliferation, migration and invasion in two ESCC cell lines (ECA109 and TE1). Conclusion: The clustered subtypes and prognostic model of DDRGs could effectively predict the prognosis and immune activity of ESCC patients. [ABSTRACT FROM AUTHOR]

Background: Radioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells. Methods: Plasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group. Results: The expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX. Conclusion: These findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells. [ABSTRACT FROM AUTHOR]

The protein expression levels of Ring finger protein 2 (RNF2) and phosphor-protein kinase B (P-AKT) were determined in esophageal squamous cell carcinoma (ESCC) tissues, and the association between patient clinicopathological characteristics and survival time following definitive intensity-modulated radiotherapy was assessed. Cancerous biopsy tissues were collected from patients with ESCC at The Fourth Affiliated Hospital of Hebei Medical University between January 2010 and December 2013. Of these 99 cases, 83 were used to analyze the protein expression level of RNF2 (89.2% positive), 85 for P-AKT (65.9% positive) and 80 for RNF2+P-AKT protein expression levels (62.5% both positive). The expression levels of RNF2 protein in ESCC were associated with tumor volume (P=0.024), whilst those of P-AKT and RNF2+PAKT were associated with sex (P=0.041 and P=0.003, respectively). There were no significant differences in overall survival (OS) or progression-free survival (PFS) rate between the RNF2− and the RNF2+-+++ groups (P=0.134 and P=0.366, respectively), or between the P-AKT− group and P-AKT+-+++ group (P=0.468; P=0.580, respectively). The 1-, 3- and 5-year OS rates were 68.0, 28.0, and 20.0%, and 86.7, 53.3, and 31.1%, in the RNF2/P-AKT+ group and Other group, respectively (χ2=4.205; P=0.040). Multivariate analysis revealed that age, T stage and RNF2+P-AKT expression were independent prognostic factors for ESCC (P=0.010, P=0.008 and P=0.010, respectively). The expression of RNF2+P-AKT combined was an independent prognostic factor affecting survival rate, and therefore presents a potential prognostic indicator for patients with ESCC, treated with definitive radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Infection of Helicobacter pylori, a major cause of various gastric diseases, has been reported to play a role in the process of tumorigenesis and progression of gastric carcinoma. Some studies have been devoted to the relationship between H. pylori infection and oesophageal cancer and have yielded conflicting results. Whether infection of H. pylori is a risk factor for this cancer remains uncertain. In this study we aimed to evaluate the association of H. pylori infection with oesophageal cancer risk. Materials and methods: The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications, then the extracted data were further analysed by systematic meta-analyses. Results: In total, 195 articles were identified, of which 12 case–control studies concerning oesophageal cancer were selected. Oesophageal adenocarcinoma risk for H. pylori infection was 0.58-fold (95% confidence interval 0.48–0.70) (Z =5.79, P <0.01) compared with the controls. Oesophageal squamous cell carcinoma risk was 0.80-fold (95% confidence interval 0.45–1.43) (Z =0.75, P >0.05) compared with the controls. Compared with CagA-negative H. pylori, CagA-positive H. pylori markedly decreased oesophageal cancer risk. Conclusion: The pooled data suggest infection of H. pylori as a possible preventive factor for oesophageal adenocarcinoma and failed to suggest a significant association between H. pylori infection and oesophageal squamous cell carcinoma. [Copyright &y& Elsevier]