BackgroundAcquired radioresistance during radiotherapy is considered as the most important reason for local tumor recurrence or treatment failure. Circular RNAs (circRNAs) have recently been identified as microRNA sponges and involve in various biological processes. The purpose of this study is to investigate the role of circRNAs in the radioresistance of esophageal cancer.MethodsTotal RNA was isolated from human parental cell line KYSE-150 and self-established radioresistant esophageal cancer cell line KYSE-150R, and hybridized to Arraystar Human circRNA Array. Quantitative real-time PCR was used to confirm the circRNA expression profiles obtained from the microarray data. Bioinformatic tools including gene ontology (GO) analysis, KEGG pathway analysis and network analysis were done for further assessment.ResultsAmong the detected candidate 3752 circRNA genes, significant upregulation of 57 circRNAs and downregulation of 17 circRNAs in human radioresistant esophageal cancer cell line KYSE-150R were observed compared with the parental cell line KYSE-150 (fold change ≥2.0 and P < 0.05). There were 9 out of these candidate circRNAs were validated by real-time PCR. GO analysis revealed that numerous target genes, including most microRNAs were involved in the biological processes. There were more than 400 target genes enrichment on Wnt signaling pathway. CircRNA_001059 and circRNA_000167 were the two largest nodes in circRNA/microRNA co-expression network.ConclusionsOur study revealed a comprehensive expression and functional profile of differentially expressed circRNAs in radioresistant esophageal cancer cells, indicating possible involvement of these dysregulated circRNAs in the development of radiation resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0977-7) contains supplementary material, which is available to authorized users.

Background Evaluating clinical outcome prior to concurrent chemoradiotherapy remains challenging for oesophageal squamous cell carcinoma (OSCC) as traditional prognostic markers are assessed at the completion of treatment. Herein, we investigated the potential of using sub-region radiomics as a novel tumour biomarker in predicting overall survival of OSCC patients treated by concurrent chemoradiotherapy. Methods Independent patient cohorts from two hospitals were included for training ( n = 87) and validation ( n = 46). Radiomics features were extracted from sub-regions clustered from patients' tumour regions using K-means method. The LASSO regression for ‘Cox’ method was used for feature selection. The survival prediction model was constructed based on the sub-region radiomics features using the Cox proportional hazards model. The clinical and biological significance of radiomics features were assessed by correlation analysis of clinical characteristics and copy number alterations(CNAs) in the validation dataset. Findings The overall survival prediction model combining with seven sub-regional radiomics features was constructed. The C-indexes of the proposed model were 0.729 (0.656–0.801, 95% CI) and 0.705 (0.628–0.782, 95%CI) in the training and validation cohorts, respectively. The 3-year survival receiver operating characteristic (ROC) curve showed an area under the ROC curve of 0.811 (0.670–0.952, 95%CI) in training and 0.805 (0.638–0.973, 95%CI) in validation. The correlation analysis showed a significant correlation between radiomics features and CNAs. Interpretation The proposed sub-regional radiomics model could predict the overall survival risk for patients with OSCC treated by definitive concurrent chemoradiotherapy. Fund This work was supported by the Zhejiang Provincial Foundation for Natural Sciences, National Natural Science Foundation of China.

BackgroundAcquired radioresistance has significantly compromised the efficacy of radiotherapy for esophageal cancer. The purpose of this study is to investigate the roles of epithelial-mesenchymal transition (EMT) and the Wnt/β-catenin signaling pathway in the acquirement of radioresistance during the radiation treatment of esophageal cancer.MethodsWe previously established a radioresistant cell line (KYSE-150R) from the KYSE-150 cell line (a human cell line model for esophageal squamous cell carcinoma) with a gradient cumulative irradiation dose. In this study, the expression of EMT phenotypes and the Wnt/β-catenin signaling pathway proteins were examined by real-time PCR, western blot and immunofluorescence in the KYSE-150R cells. The KYSE-150R cells were then treated with a β-Catenin/Tcf inhibitor FH535. The expressions of nuclear and cytoplasmic β-catenin and EMT markers in KYSE-150R cells were assessed at both mRNA and protein level after FH535 treatment. The radiosensitization effect of FH535 on KYSE-150R was evaluated by CCK8 analysis and a colony forming assay. DNA repair capacities was detected by the neutral comet assays.ResultsKYSE-150R cell line displayed obvious radiation resistance and had a stable genetic ability. EMT phenotype was presented in the KYSE-150R cells with decreased E-cadherin and increased snail and twist expressions. The up-regulated expressions of Wnt/β-catenin signaling pathway proteins (Wnt1, FZD1-4, GSK3β, CTNNB1 and Cyclin D1), the increased phosphorylation of GSK3β, and the decreased phosphorylation of β-catenin were observed in KYSE-150R cells compared with KYSE-150 cells, implicating the activation of the Wnt pathway in KYSE-150R cells. The expression of nuclear β-catenin and nuclear translocation of β-catenin from the cytoplasm was decreased after FH535 treatment. FH535 also reversed EMT phenotypes by increasing E-cadherin expression. The cell proliferation rates of KYSE-150R were dose-dependent and the radiation survival fraction was significantly decreased upon FH535 treatment. Neutral comet assays indicated that FH535 impairs DNA double stranded break repair in KYSE-150R cells.ConclusionsAcquisition of radioresistance and EMT in esophageal cancer cells is associated with the activation of the Wnt/β-catenin pathway. EMT phenotypes can be reduced and the radiosensitivity of esophageal cancer cells can be enhanced by inhibiting the Wnt/β-catenin pathway with FH535 treatment.

Abstract. The aim of this study was to determine the prognostic factors and their significance in gastric cancer (GC) patients, using the artificial neural network (ANN) and Cox regression hazard (CPH) models. A retrospective analysis was undertaken, including 289 patients with GC who had undergone gastrectomy between 2006 and 2007. According to the CPH analysis, disease stage, peritoneal dissemination, radical surgery and body mass index (BMI) were selected as the significant variables. According to the ANN model, disease stage, radical surgery, serum CA19-9 levels, peritoneal dissemination and BMI were selected as the significant variables. The true prediction of the ANN was 85.3% and of the CPH model 81.9%. In conclusion, the present study demonstrated that the ANN model is a more powerful tool in determining the significant prognostic variables for GC patients, compared to the CPH model. Therefore, this model is recommended for determining the risk factors of such patients.

Radioresistance is considered as the most important reason for local tumour recurrence. This study investigates the role of miRNAs in radioresistant human esophageal cancer cells. Human miRNA microarray has been used to detect the differential expressed microRNAs between radioresistant esophageal cell line KYSE-150R and the parental cell line KYSE-150. The relative expression of some candidate miRNAs was measured by quantitative real-time PCR (qRT-PCR). Potential mRNA targets were analysed bioinformatically. Significant upregulation of 10 microRNAs and downregulation of 25 microRNAs were detected. The statistical significance of downregulation in hsa-miR-301a, hsa-miR-141 and hsa-miR-18b expression (P < 0.05) were confirmed by qRT-PCR. The correlation of the predicted microRNA target genes to apoptosis (63 genes), cell cycle (67 genes), DNA damage and repair (18 genes) were confirmed by functional annotation. The downregulation of hsa-miR-301a promoted radioresistance in KYSE-150R through the upregulation of wnt1, indicating that wnt/β-catenin signal pathway might be important in radioresistance. In conclusion, a unique set of miRNAs and their expression profiles in radiation resistance have been identified, providing a solid basis for future studies to investigate the target genes of these miRNAs and their function.

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A phase III randomized study on the efficacy and safety of consolidation chemotherapy with paclitaxel plus cisplatin following radical hysterectomy and adjuvant chemoradiotherapy (CRT) in the treatment of high risk early-stage cervical cancer were reported. 146 eligible patients were randomized to arm A receiving concurrent CRT or arm B receiving CRT plus consolidation chemotherapy, respectively. An interim analysis showed a trend of improvement on disease-free survival (DFS) and overall survival (OS) in arm B with hazard ratios (HR) of 1.25 (95% CI = 0.60–2.60, p = 0.55) and 1.43 (95% CI = 0.64–3.20, p = 0.38) for DFS and OS, respectively. The 3-year DFS and OS were 82.0% vs.74.3%, and 86.6% vs. 78.3% for patients receiving CRT plus consolidation chemotherapy and CRT alone, respectively. There was significant difference between the two arms in distant alone recurrence (p = 0.048). Multivariate analysis indicated that pathologic type was a significant prognostic factor for OS (p = 0.045), positive pelvic nodes were significantly associated with both OS (p=0.02) and DFS (P=0.03). Grade 2 to 4 gastrointestinal disorder (p = 0.95), radiation enteritis (P=0.48), radiation cystitis (p = 0.27) and radioepidermitis (p = 0.46) were similar in the two arms. Overall rates of grade 0–2/3–4 myelosuppression were 87.7%/12.3% for arm A and 74.6%/25.4% for arm B, respectively, but this difference was not statistically significant (p = 0.05). In conclusion, concurrent CRT plus consolidation chemotherapy may play a potential role in further improving survival outcomes for high-risk early stage cervical cancer patients compared CRT alone.

BackgroundJuglans regia has been found to exhibit significant anticancer activity against various human cancer cell lines. This study was undertaken to isolate the active chemical constituent (Juglone) and to investigate its cytotoxic activity along with its various analogs against different human cancer cell lines.MethodsIsolation of juglone, a napthoquinone, from the chloroform extract of the root part of Juglans regia was executed by flash chromatography using silica gel as stationary phase. The isolated Juglone was used as starting material for the further synthesis of a novel series of triazolyl analogs using click chemistry approach to investigate their cytotoxic potential against different human cancer cell lines using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay.ResultsThe different extracts of Juglans regia and the isolated compound (juglone) exhibited satisfactory cytotoxic activity against a panel of eight different human cancer cell lines namely, prostate colon (Colo-205 and HCT-116), breast (T47D), prostate (PC-3 and DU-145), skin (A-431) and lung (NCI-H322 and A549). Interestingly, all the synthesised analogs displayed enhanced and selective cytotoxic activity against lung cancer cell lines only. Of the synthesized derivatives, 15a and 16a displayed the best activity with IC50 of 4.72 and 4.67 μM against A549 cells. Both these derivatives exhibited superior potency to BEZ-235 against both the lung cancer cell lines. So far as the structural aspects are concerned, electron withdrawing substituents at the ortho position of R moiety of the triazolyl analogs seem to be essential for attaining better activity.ConclusionThe present study demonstrates the selective and enhanced cytotoxic activity of the triazolyl analogs of juglone against NCI-H322 and A549 human lung cancer cell lines. Some derivatives exhibited superior potency to BEZ-235, a commercially available anticancer agent.