Hsa_circ_0014879 regulates the radiosensitivity of esophageal squamous cell carcinoma through miR-519-3p/CDC25A axis.

Circular RNAs (circRNAs) play critical roles in regulating the radiosensitivity of various cancers, including esophageal squamous cell carcinoma (ESCC). This research aimed to explore the role and potential mechanism of hsa_circ_0014879 in regulating ESCC radioresistance. The levels of hsa_circ_0014879, microRNA-519-3p (miR-519-3p) and cell division cycle 25A (CDC25A) were measured using quantitative real-time PCR or western blot. Cell proliferation was evaluated by colony formation assay. Cell migration and invasion were assessed by transwell and scratch assays. The levels of epithelial-mesenchymal transition (EMT)-related proteins were detected by western blot. Xenograft assay was used to analyze the effect of hsa_circ_0014879 on radiosensitivity in vivo. The binding relationship among hsa_circ_0014879, miR-519-3p and CDC25A was confirmed by dual-luciferase reporter assay. Hsa_circ_0014879 and CDC25A were upregulated, whereas miR-519-3p was downregulated in radio-resistant ESCC tissues and cells. Depletion of hsa_circ_0014879 suppressed the proliferation, migration and invasion of radio-resistant ESCC cells. Hsa_circ_0014879 knockdown elevated radiosensitivity of radio-resistant cells by modulating miR-519-3p. Moreover, miR-519-3p enhanced the radiosensitivity of radio-resistant cells by targeting CDC25A. Also, hsa_circ_0014879 upregulated CDC25A via sponging miR-519-3p. Hsa_circ_0014879 silencing enhanced the radiosensitivity of ESCC via regulating the miR-519-3p/CDC25A pathway.

Prognostic value of neutrophil-to-lymphocyte ratio in peripheral blood and pathological tissue in patients with esophageal squamous cell carcinoma.

The aim of this study was to investigate the prognostic value of neutrophils-to-lymphocyte ratio in peripheral blood (NLR) and in cancer nest (iNLR) in patients with esophageal squamous cell carcinoma (ESCC).Totally 103 patients with ESCC treated with surgical radical surgery in the Shuyang People's Hospital from February 2010 to November 2014 were collected retrospectively. Peripheral blood routine test and immunohistochemistry examination of carcinoma nest were mainly performed. Survival rates were analyzed with Kaplan-Meier curves. Univariate analysis and multivariate analysis were also performed to explore potential prognostic factors of ESCC.The median survival time after surgery of low NLR group and high NLR group were 48 months and 30 months, respectively. The difference of overall survival between the 2 groups was statistically significant (χ = 7.435, P = .006). The median survival time after surgery of low iNLR group and high iNLR group were 37 months and 24.5 months, respectively. The difference between the 2 groups was also statistically significant (χ = 33.640, P = .000). Univariate analysis showed influence factors of postoperative survival in patients with ESCC included tumor-node-metastasis staging, NLR, iNLR, and grade of NLR score + iNLR score (P ≤ .05). Multivariate analysis confirmed NLR, iNLR, and tumor-node-metastasis staging were independent influence factors of postoperative survival in patients with ESCC (P ≤ .05).High level of NLR and iNLR implies a poor prognosis of ESCC. The application of both NLR and iNLR could guide clinicians to take aggressive treatments for high risk population.

Cytoskeleton-associated protein 4 is a novel serodiagnostic marker for esophageal squamous-cell carcinoma.

BACKGROUND: Recent years have witnessed significant progress in the treatment of esophageal squamous-cell carcinoma (ESCC); however, the prognosis of ESCC is still unsatisfactory. Bio-markers are required to improve identification of high-risk populations and help management of ESCC. This study was to evaluate the role of serum CKAP4 in ESCC. METHODS: This longitudinal study recruited 207 ESCC patients and age-/sex-matched healthy controls. Circulating levels of CKAP4 were measured using ELISA kits, while the expression of CKAP4 in esophageal tissue was evaluated using Western blotting. RESULTS: Serum CKAP4 levels were higher in ESCC patients (380.2±171.3 pg/mL) than healthy controls (271.8±97.4 pg/mL; P<0.001). The area under the receiver-operating characteristic curve of serum CKAP4 levels to identify the presence of ESCC was 0.675 (95% CI 0.622-0.728; P<0.001). According to Youden's index, the best cutoff value was 429.1 pg/mL (sensitivity 0.415 and specificity 0.995). Furthermore, after follow-up, multivariate analyses identified that pathological lymph node metastases were the poorest prognostic factor (HR 1.862, 95% CI 1.093-3.173; P=0.022), followed by serum CKAP4 (HR 1.437, 95% CI 1.025-2.014; P=0.035). When stratified by tertiles of serum CKAP4, subjects in the first tertile presented a mean survival time of 75.4 months (95% CI 68.0-81.9), which decreased significantly in the second tertile (73.8 months, 95% CI 61.4-86.3) and the third tertile (59.9 months, 95% CI 49.8-70.0, log-rank χ 2=8.235; P=0.016). CONCLUSION: These results suggested that serum CKAP4 could be a potential biomarker for clinical management of ESCC.

Expression of the CD59 Glycoprotein Precursor is Upregulated in an Estrogen Receptor-alpha (ER-α)-Negative and a Tamoxifen-Resistant Breast Cancer Cell Line In Vitro.

BACKGROUND Breast cancer is the most prevalent cancer and the leading cause of cancer death among women. Tamoxifen (TAM) therapy is one of the most widely and successfully used endocrine treatments for estrogen receptor α (ERα)-positive breast cancer. However, resistance to TAM has been a major challenge. In addition, the mechanisms underlying endocrine resistance remain unclear. Here, we report that CD59, a phosphatidylinositol-anchored glycoprotein, is a candidate resistant gene for TAM therapies. MATERIAL AND METHODS The breast cancer cell line MCF-7, the MCF-10A cell line, and the TAM-resistant breast cancer cell line TAMR-MCF-7 were cultured. The TAMR-MCF-7 cells were transfected with CD59 siRNA and control siRNA. Then, the CD59 glycoprotein precursor expression was detected by reverse transcription­quantitative polymerase chain reaction and western blot analysis. Cell counting kit-8 and flow cytometry assay were performed to examine cell proliferation, cell apoptosis, and cell cycle. In addition, the expressions of Bax, Bcl2, cleaved-caspase-8, cleaved-caspase-6, cleaved-caspase-3, and cleaved-PARP were analyzed by western blot analysis in the TAMR-MCF-7 cells treated with CD59 siRNA. RESULTS In the present study, we found that the CD59 glycoprotein precursor was aberrantly upregulated in the ERα-negative breast cancer MCF-10A cells but not the MCF-7 cells. Furthermore, the CD59 glycoprotein precursor expression was elevated in the TAM-resistant breast cancer cells. Importantly, RNAi-mediated attenuation of CD59 was sufficient to rescue the resistance to TAM in the TAMR-MCF-7 cells. CONCLUSIONS In summary, our results proposed a candidate biomarker for predicting TAM resistance in ERa-positive breast cancer via targeting CD59, therefore it could be a novel therapeutic option.

Pyrroloquinoline quinone induces chondrosarcoma cell apoptosis by increasing intracellular reactive oxygen species.

Pyrroloquinoline quinone (PQQ) has been reported to contribute to cancer cell apoptosis and death; however, little is known of its underlying mechanisms. The present study was designed to investigate the role of PQQ in chondrosarcoma cell apoptosis and the underlying mechanism. A cell cytotoxicity assay was used to detect cell death; flow cytometry analysis was also performed to determine cell apoptosis and intracellular reactive oxygen species (ROS). Biochemical methods were employed to detect the activity and the expression of superoxide dismutase (SOD)1, SOD2 and glutathione. The present study also examined the effect on tumorigenesis in vivo. The results demonstrated that the apoptosis of SW1353 cells induced by PQQ increased in a concentration­ and time­dependent manner, which may be attributable to the accumulation of intracellular ROS. In the in vivo experiments, PQQ inhibited proliferation and promoted apoptosis, increased ROS levels and caused DNA damage in transplanted cells. Taken together, the findings of the present study confirmed that PQQ induced apoptosis in human chondrosarcoma SW1353 cells and transplanted cells, by increasing intracellular ROS and reducing the ability of scavenging oxygen free radicals.

Expression and clinical significance of vascular endothelial growth factor and fms-related tyrosine kinase 1 in colorectal cancer.

The aim of the present study was to investigate the prognostic value of vascular endothelial growth factor (VEGF) and its receptor, fms-related tyrosine kinase-1 (FLT-1), in patients with colorectal cancer. An immunohistochemical approach was used to detect the protein expression of VEGF and FLT-1 in 90 patients with colorectal cancer. The impact of VEGF and FLT-1 tumor cell expression, in addition to other factors, on overall survival (OS) was retrospectively assessed in 90 patients. Multivariate analysis was performed in order to determine the prognostic significance of the factors. The positive expression rate of VEGF in the colorectal cancer tissues was 62.2% (56/90). The positive expression rate of FLT-1 in colorectal cancer tissues was 48.9% (44/90). The results of the log-rank test revealed that improved OS rates were significantly associated with the absence of VEGF expression (P<0.0001). By contrast, FLT-1 expression had no significant impact on OS (P=0.289). Upon multivariate analysis, VEGF expression (P=0.038) and clinical stage (P=0.021) maintained significance. VEGF expression proved to be an independent negative predictor of OS in patients with colorectal cancer. Conversely, FLT-1 expression demonstrated no impact on OS.

Phase II trial of concurrent chemoradiotherapy with S-1 versus weekly cisplatin for locoregionally advanced nasopharyngeal carcinoma.

This is a prospective randomized trial performed to compare the efficacy of concurrent chemoradiotherapy (CCRT) + S-1 (oral fluoropyrimidine) with that of CCRT + cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 105 eligible patients were randomly assigned to receive CCRT with S-1 (S-1 arm, n=50) or cisplatin weekly (control arm, n=55). Patients in the S-1 arm received CCRT plus S-1 (40-60 mg, twice daily for 4 consecutive weeks. Patients in the control arm received standard CCRT with weekly cisplatin. All the patients were included in an intention-to-treat survival analysis. Our results demonstrated that the S-1 and control arms did not differ significantly in terms of complete response, partial response, progression-free survival or overall survival (all P-values >0.05). However, the two arms varied significantly regarding certain grade 3-4 toxicities, including leukopenia, 5.5 vs. 22.0% (P=0.013); mucositis, 20.0 vs. 46.0% (P=0.004); dermatitis, 15.5 vs. 32.7% (P=0.011); and nausea, 9.1 vs. 41.6% (P<0.001) for the S-1 and control arms, respectively. In conclusion, CCRT with S-1 was found to be similar in efficacy but superior in terms of toxicity compared to the standard CCRT with weekly cisplatin.

Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/mTOR signaling.

Temozolomide (TMZ), a DNA alkylating agent, represents the most important chemotherapeutic option for the treatment of glioblastoma in the clinic. Despite its frequent use, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioblastoma. Previous evidence suggested that curcumin (CUM), an ingredient of the Indian spice turmeric, is able to sensitize glioblastoma to TMZ treatment. However, the underlying molecular mechanism remains elusive. In the present study, we performed in vitro and in vivo experiments to evaluate the interaction of CUM and TMZ on the inhibition of glioblastoma and to investigate its potential mechanisms of action using U87MG cell lines and xenograft mouse models. We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis. We then proceeded to investigate the potential apoptotic signaling pathways that are involved. We observed a synergistic effect of the combination of CUM and TMZ in generating reactive oxygen species (ROS) production, suggesting that ROS may contribute to the impact of CUM on sensitizing TMZ treatment. We also showed that CUM and TMZ treatment alone significantly suppressed phosphorylated AKT and mTOR, whereas their combination achieved a more pronounced inhibitory effect. These data indicated that blockage of AKT/mTOR signaling appeared to contribute to the elevated apoptosis caused by the combination treatment with CUM and TMZ. In conclusion, this study provided molecular insights into the effects of CUM on the therapeutic response of glioblastoma to TMZ and opened new avenues for optimizing the therapeutic effects of TMZ-based therapies.