Description: Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation, Published online: 21 March 2018; doi:10.1038/s41388-018-0169-4 Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation

Description: We report that odd-skipped related 1 ( OSR1 ) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or downregulated in gastric cancer cell lines. OSR1 expression was also significantly downregulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or downregulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested cell cycle, and induced apoptosis in gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1 -short hairpin RNA significantly enhanced cell growth, promoted cell cycle, and inhibited apoptosis in normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated the p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and Western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5 and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in p53 signaling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in Wnt/β-catenin signaling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulfite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan-Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stages I-III patients. In conclusion, OSR1 acts as a functional tumor suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of early stage of gastric cancer.

Description: Climate, Vol. 5, Pages 55: An Ecological Study of the Association between Area-Level Green Space and Adult Mortality in Hong Kong Climate doi: 10.3390/cli5030055 Authors: Lixia Xu Chao Ren Chao Yuan Janet Nichol William Goggins There is evidence that access to green spaces have positive effects on health, possibly through beneficial effects on exercise, air quality, urban heat islands, and stress. Few previous studies have examined the associations between green space and mortality, and they have given inconsistent results. This ecological study relates green space to mortality in Hong Kong from 2006 to 2011. The Normalized Difference Vegetation Index (NDVI), a measure of green space coverage, was measured for 199 small geographic areas in Hong Kong. Negative Binomial Regression Models were fit for mortality outcomes with NDVI, age, gender, population density, and area-level socio-economic variables as predictors, with Generalized Estimating Equations used to control for within-cluster correlation. An interquartile range (0.44 units) higher NDVI was significantly associated with lower cardiovascular (relative risk (RR) = 0.88, 95% confidence interval (CI) = 0.80, 0.98) and diabetes (RR = 0.72, 95% CI = 0.60, 0.92) mortality, and non-significantly associated with lower chronic respiratory mortality (RR = 0.90, 95% CI = 0.79, 1.02). Associations were stronger for males and low-income area residents. Lung cancer mortality had no significant association with green space. Better provision of urban green space, particularly in low-income areas, appears to have potential to reduce mortality in densely-populated Asian cities.

Description: Objective: Approximately 50% of hepatocellular carcinomas(HCCs) recur within 2 years after radiofrequency ablation (RFA).Cancer stem cells (CSCs) may play a critical role in the processof intrahepatic metastasis. Methods: We evaluated the migration and proliferation ofHCC cell lines after sublethal heat treatment by performingtranswell and cell counting assays. We subsequently evaluatedthe expression of CD133, CD44, and EpCAM in these heat-treated cells using Western blot, qRT-PCR, and flow cytometry.Capacity of sphere formation in vitro and tumor initiationin vivo were also assessed. Furthermore, enzyme-linkedimmunosorbent assay was performed to confirm vascularendothelial growth factor (VEGF) secretion in heat-treatedcells. Recombinant VEGF and VEGFR2 inhibitor SU1498 wereadded to the culture medium of HCC cell lines to examinethe stimulatory effect of VEGF and the combinative effectof VEGF stimulation and VEGFR2 inhibition. The effect ofVEGFR1 stimulation was subsequently detected by adding itsligand placental growth factor (PlGF). Finally, we investigatedthe pivotal role of VEGFR1 by adding PlGF or/and neutralizingantibody to VEGFR1. Results: We found increased migration and decreasedproliferation in the HepG2, HCCLM3, and SMMC7721cell lines after sublethal heat treatment, which coincidedwith increased expression of CD133, CD44, and EpCAMand increased sphere formation. Tumor initiation assays inHCCLM3 cells indicated a higher cancer stem cell frequencyafter sublethal heat treatment. Western blot and flow cytometryshowed that VEGFR1 was unregulated after sublethal heattreatment, which is correlated with enhanced stemness andmigration. Further exploration revealed that HCC cellssecreted more VEGF after heat treatment. VEGF promotedthe stemness and migration of HCC cells, which could notbe reduced by inhibiting VEGFR2. Inhibition of VEGFR2could also not reduce the stemness and migration of HCCcells with heat treatment. In contrast, PlGF enhanced thestemness and migration of HCC cells in a VEGFR1-dependentmanner, which is similar to the results seen with sublethal heattreatment. Blocking VEGFR1 reduced heat-induced stemnessand migration. Conclusions: Sublethal heat treatment can increase themigration capability and stem cell-like phenotype of HCC celllines. VEGFR1 may play a critical role in such a malignantchange after sublethal heat treatment, suggesting VEGFR1 asa potential and promising therapeutic target for inhibitingintrahepatic metastasis after RFA. DOI: 10.20892/j.issn.2095-3941.2018.S100

Description: Objective: Limited effective interventions for advancedhepatocellular carcinoma (HCC) are available. This studyaimed to investigate the potential clinical utility of apatinib,a highly selective inhibitor of the vascular endothelial growthfactor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. Methods: Four human HCC cell lines (SMMC-7721, HCCLM3,MHCC-97H, and Hep-3B) were treated with apatinib,irradiation, or combination treatment. Clonogenic formationassays, flow cytometry, and examination of nuclear γ-H2AXfoci were performed. Xenograft mouse models were used toassess the impact of combination treatment on tumor growth. Results: Clonogenic formation assays revealed apatinibenhanced the radiosensitivity of HCC cell lines. The combinedtreatment of apatinib and radiation promoted G2/M arrestinduced by irradiation in HCC cells. Flow cytometry analysisshowed that apatinib promoted radiation-induced apoptotic celldeath. Immunofluorescence showed that apatinib increased theaverage number of γ-H2AX foci after irradiation. In mice withestablished HCC tumor xenografts, apatinib combined withirradiation significantly decreased tumor growth. Conclusions: Our results demonstrate that apatinib enhances theradiosensitivity of HCC cells by enhancing irradiation-inducedapoptosis, delaying DNA damage repair in vivo and in vitro. DOI: 10.20892/j.issn.2095-3941.2018.S102