Overcoming radio-resistance in esophageal squamous cell carcinoma via hypermethylation of PIK3C3 promoter region mediated by KDM5B loss.

Many patients with esophageal squamous cell carcinoma (ESCC) are inoperable because of old age or the advanced stage of the disease; thus radio- and chemotherapy are believed as the standard treatments for these patients. However, due to the radio-resistance of tumor cells that may develop during radiotherapy, results remain unsatisfactory. In this article, the possible relationship between the expression of lysine demethylase 5B (KDM5B) and ESCC radio-resistance is clarified, and the underlying mechanism is evaluated. Using the GSE75241 microarray, we identified KDM5B as a potential oncogene in ESCC. KDM5B was overexpressed in ESCC patients and cells. Inhibition of KDM5B enhanced the H3K4me3 methylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) promoter and induced the expression of PIK3C3. Knockdown of KDM5B or overexpression of PIK3C3 in KYSE-150 and TE-10 cells promoted apoptosis, cell cycle arrest, autophagy, and increased sensitivity to radiotherapy. Silencing of PIK3C3 attenuated the promoting effect of sh-KDM5B on the sensitivity of ESCC cells to radiotherapy. The inhibition of sh-KDM5B in radio-resistance of ESCC cells was also reproduced in vivo. Taken together, our findings provide evidence that reduced expression of KDM5B has a critical role in promoting ESCC radio-sensitivity by upregulating PIK3C3, suggesting KDM5B may function as an oncogene in ESCC.

PIK3C3 Acts as a Tumor Suppressor in Esophageal Squamous Cell Carcinoma and Was Regulated by MiR-340-5p.

BACKGROUND Esophageal squamous cell carcinoma (ESCC), a major histological subtype of esophageal cancer, is a common cause of tumor-related deaths in the world. Due to the lack of understanding of the pathogenesis of ESCC, its clinical treatment is still a big challenge. In the present study, we aimed to identify an ESCC-related gene in the GEO dataset, and to explore its function and mechanism in ESCC. MATERIAL AND METHODS The GSE dataset (GSE100492) consisting of 10 samples was analyzed using GEO2R for identifying the differentially expressed genes between ESCC and normal samples. Expression levels of mRNA and miRNA in ESCC tissues and cells were detected via quantitative real-time polymerase chain reaction. Protein expression was analyzed by western blot. Cell proliferation viability was determined through MTT and colony formation. Cell distribution and apoptosis was detected by flow cytometry. MiRNA target prediction was analyzed by bioinformatics. The interplay between miR-340-5p and PIK3C3 was validated by dual-luciferase reporter assay. RESULTS PIK3C3 was lowly expressed in ESCC tissue and indicated a poor prognosis in patents. Overexpression of PIK3C3 in vitro repressed cell proliferation of KYSE-150 and TE-12 cells. Moreover, PIK3C3 overexpression was demonstrated to enhance the sensitivity of KYSE-150 and TE-12 cells to irradiation. In addition, miR-340-5p was revealed to directly bind and negatively modulate PIK3C3 expression in ESCC. Blockage of miR-340-5p promoted ESCC cell proliferation, while rescue of PIK3C3 reversed this effect. MiR-340-5p was highly expressed in ESCC tissue and it exhibited a negative correlation with PIK3C3 expression. CONCLUSIONS MiR-340-5p functioned as an oncogene of ESCC by directly binding and repressing the expression of PIK3C3.

Impact of radiotherapy on immunological parameters, levels of inflammatory factors, and clinical prognosis in patients with esophageal cancer.

The aim of this study was to observe dynamic changes in immunological parameters and levels of inflammatory factors from pre-radiotherapy to post-radiotherapy in patients with esophageal cancer, and to evaluate the related clinical prognosis. In all, 110 patients with esophageal cancer who underwent radiotherapy were enrolled. Before radiotherapy, post-radiotherapy, and 3 months after radiotherapy, the percentages of T lymphocyte subsets and natural killer (NK) cells in peripheral blood were detected using flow cytometry. The levels of serum inflammatory factors were measured with the enzyme-linked immunosorbent assay (ELISA). Thirty peripheral blood samples from healthy people were similarly analysed as the control. Before radiotherapy, the percentages of CD4+ and CD8+ T cells and NK cells, and the CD4+/CD8+ rate in esophageal cancer patients were significantly different from those in the healthy control group (P < 0.001); the levels of inflammatory factors were increased significantly (P < 0.001). The percentages of the above cells and the levels of inflammatory factors also differed statistically significantly between pre- and post-radiotherapy (P < 0.001) in the esophageal cancer patients. Three months after radiotherapy, the percentages of CD3+ (P = 0.453), CD4+ (P = 0.108), and CD8+ T cells (P = 0.163) and NK cells (P = 0.103) had recovered to the level before radiotherapy; and the levels of TNF-α (P = 0.101), IL-6 (P = 0.302) and IL-8 (P = 0.250) were also restored. After radiotherapy, alterations in immunological parameters were associated with the irradiation volume and the myelosuppression condition. Patients with recovered immunological parameters showed a longer median survival time than those with poor recovery of immunological parameters. For esophageal cancer patients who were immunosuppressive and had an activated inflammatory response before radiotherapy, radiotherapy aggravated these symptoms, and this aggravation was positively associated with myelosuppression and irradiation volume. In addition, recovery of the immunological parameters indicated better prognosis.

Association between the Functional Polymorphism of Vascular Endothelial Growth Factor Gene and Breast Cancer: A Meta-Analysis.

The vascular endothelial growth factor (VEGF) gene single-nucleotide polymorphism involved in the regulation of the protein levels has been implicated in breast cancer. However, the published studies have produced contentious and controversial results. Herein, we performed a meta-analysis (from January to October 2013); to further evaluate the association between +936 C/T polymorphism and the risk of breast cancer. By searching the EMBASE, PubMed, and Web of Science databases, we identified a total of 12 case-control studies with 8,979 cancer patients and 9,180 healthy controls. The strength of the association was assessed using Odds Ratios (ORs) with 95% Confidence Intervals (CI). We found no evidence indicating that the allelic model or the genotype models of +936 C/T polymorphism were associated with the risk of breast cancer in total population (ORCC vs. TT=1.01, 95% CI=0.96-1.06, Ph=1.00; ORCC+CT vs. TT=1.00, 95% CI=0.96-1.05, Ph=1.00; ORCC vs. CT+TT=1.02, 95% CI=0.98-1.07, Ph=0.94; OR allele C vs. allele T=1.01, 95% CI=0.98-1.04, Ph=0.99; ORCT vs. TT=1.01, 95% CI=0.93-1.09, Ph=1.00). Such lack of association with breast cancer was also observed in subgroup analyses according to ethnicity as well as in the analysis by source of controls. In conclusion, this meta-analysis suggests that the functionally important +936 C/T polymorphism may not be associated with breast cancer risk. Larger well-designed studies with gene-to-gene and gene-to-environment interactions are clearly required to validate the results further.

Dose level of occupational exposure in China.

This paper discusses the dose level of Chinese occupational exposures during 1986-2000. Data on occupational exposures from the main categories in nuclear fuel cycle (uranium enrichment and conversion, fuel fabrication, reactor operation, waste management and research activity, except for uranium mining and milling because of the lack of data), medical uses of radiation (diagnostic radiation, nuclear medicine and radiotherapy) and industrial uses of radiation (industrial radiography and radioisotope production) are presented and summarised in detail. These are the main components of occupational exposures in China. In general, the average annual effective doses show a steady decreasing trend over periods: from 2.16 to 1.16 mSv in medical uses of radiation during 1990-2000; from 1.92 to 1.18 mSv in industrial radiography during 1990-2000; from 8.79 to 2.05 mSv in radioisotope production during the period 1980-2000. Almost all the average annual effective doses in discussed occupations were lower than 5 mSv in recent years (except for well-logging: 6.86 mSv in 1999) and no monitored workers were found to have received the occupational exposure exceeding 50 mSv in a single year or 100 mSv in a five-year period. So the Chinese protection status of occupation exposure has been improved in recent years. However, the average annual effective doses in some occupations, such as diagnostic radiology and coal mining, were still much higher than that of the whole world. There are still needs for further improvement and careful monitoring of occupational exposure to protect every worker from excessive occupational exposure, especially for the workers who were neglected before.