AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cel...AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC 50 ) and reversal index (IC 50 in experimental group/IC 50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 μmol/L in HepG2/OXA cells, the IC 50 decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/ OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.展开更多
OBJECTIVE： To evaluate the association of X-ray cross-complementing group 1 （XRCC1） Arg399GIn, Arg194Trp and Arg280His polymorphisms with the risk of glioma. DATA SOURCES： A systematic literature search of papers ...OBJECTIVE： To evaluate the association of X-ray cross-complementing group 1 （XRCC1） Arg399GIn, Arg194Trp and Arg280His polymorphisms with the risk of glioma. DATA SOURCES： A systematic literature search of papers published from January 2000 to August 2012 in PubMed, Embase, China National Knowledge Infrastructure database, and Wanfang da- tabase was performed. The key words used were ＂glioma＂, ＂polymorphism＂, and ＂XRCC1 or X-ray repair cross-complementing group 1＂. References cited in the retrieved articles were screened manually to identify additional eligible studies. STUDY SELECTION： Studies were identified according to the following inclusion criteria： case-control design was based on unrelated individuals; and genotype frequency was available to estimate an odds ratio （OR） and 95% confidence interval （CI）. Meta-analysis was performed for the selected studies after strict screening. Dominant and recessive genetic models were used and the relationship between homozygous mutant genotype frequencies and mutant gene frequency and glioma incidence was investigated. We chose the fixed or random effect model according to the heterogeneity to calculate OR and 95%CI, and sensitivity analyses were conducted. Publication bias was examined using the inverted funnel plot and the Egger＇s test using Stata 12.0 software. MAIN OUTCOME MEASURES： Association of XRCC1 Arg399GIn, Arg194Trp, and Arg280His polymorphisms with the risk of glioma, and subgroup analyses were performed according to differ- ent ethnicities of the subjects.RESULTS： Twelve articles were included in the meta-analysis. Eleven of the articles were concerned with the Arg399GIn polymorphism and glioma onset risk. Significantly increased glioma risks were found only in the dominant model （Gin/Gin ＋ GIn/Arg versus Arg/Arg： OR = 1.26, 95%CI= 1.03-1.54, P = 0.02）. In the subgroup analysis by ethnicity, significantly increased risk was found in Asian subjects in the recessive （OR = 1.46, 95%CI= 1.04-2.45, P = 0.03） and dominant models （OR = 1.40, 95%CI= 1.10-1.78, P = 0.007）, and homozygote contrast （OR = 1.69, 95%CI= 1.17-2.45, P = 0.005）, but not in Caucasian sub- jects. For association of the Arg194Trp （eight studies） and Arg280His （four studies） polymorphisms with glioma risk, the meta-analysis did not reveal a significant effect in the allele contrast, the recessive genetic model, the dominant genetic model, or homozygote contrast. CONCLUSION： The XRCC1 Arg399GIn polymorphism may be a biomarker of glioma susceptibility, espe- cially in Asian populations. The Arg194Trp and Arg280His polymorphisms were not associated with overall glioma risk.展开更多
基金Supported by National Natural Sciences Foundation of China,No. 81001067the Ministry of Science and Technology International Cooperation Project, No. 2010DFA31870the AstraZeneca Special Research Foundation for Targeted Therapy of the Wu Jieping Medical Foundation, No. 320.6700.09068
文摘AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 μmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC 50 ) and reversal index (IC 50 in experimental group/IC 50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 μg/mL and 10 μmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross-complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 μmol/L in HepG2/OXA cells, the IC 50 decreased to 39.65 μmol/L after treatment with 10 μmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/ OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway.
基金The Fundamental Research Funds for Jilin University in China,No.450060445246the High-Tech Industrial Development Project of Jilin Province in China,No.20090633+1 种基金the Scientific Research Foundation of Jilin Province in China,No.20130206001YY,20120713 and 200905169the Scientific Research Foundation of Changchun in China,No.12SF29
文摘OBJECTIVE： To evaluate the association of X-ray cross-complementing group 1 （XRCC1） Arg399GIn, Arg194Trp and Arg280His polymorphisms with the risk of glioma. DATA SOURCES： A systematic literature search of papers published from January 2000 to August 2012 in PubMed, Embase, China National Knowledge Infrastructure database, and Wanfang da- tabase was performed. The key words used were ＂glioma＂, ＂polymorphism＂, and ＂XRCC1 or X-ray repair cross-complementing group 1＂. References cited in the retrieved articles were screened manually to identify additional eligible studies. STUDY SELECTION： Studies were identified according to the following inclusion criteria： case-control design was based on unrelated individuals; and genotype frequency was available to estimate an odds ratio （OR） and 95% confidence interval （CI）. Meta-analysis was performed for the selected studies after strict screening. Dominant and recessive genetic models were used and the relationship between homozygous mutant genotype frequencies and mutant gene frequency and glioma incidence was investigated. We chose the fixed or random effect model according to the heterogeneity to calculate OR and 95%CI, and sensitivity analyses were conducted. Publication bias was examined using the inverted funnel plot and the Egger＇s test using Stata 12.0 software. MAIN OUTCOME MEASURES： Association of XRCC1 Arg399GIn, Arg194Trp, and Arg280His polymorphisms with the risk of glioma, and subgroup analyses were performed according to differ- ent ethnicities of the subjects.RESULTS： Twelve articles were included in the meta-analysis. Eleven of the articles were concerned with the Arg399GIn polymorphism and glioma onset risk. Significantly increased glioma risks were found only in the dominant model （Gin/Gin ＋ GIn/Arg versus Arg/Arg： OR = 1.26, 95%CI= 1.03-1.54, P = 0.02）. In the subgroup analysis by ethnicity, significantly increased risk was found in Asian subjects in the recessive （OR = 1.46, 95%CI= 1.04-2.45, P = 0.03） and dominant models （OR = 1.40, 95%CI= 1.10-1.78, P = 0.007）, and homozygote contrast （OR = 1.69, 95%CI= 1.17-2.45, P = 0.005）, but not in Caucasian sub- jects. For association of the Arg194Trp （eight studies） and Arg280His （four studies） polymorphisms with glioma risk, the meta-analysis did not reveal a significant effect in the allele contrast, the recessive genetic model, the dominant genetic model, or homozygote contrast. CONCLUSION： The XRCC1 Arg399GIn polymorphism may be a biomarker of glioma susceptibility, espe- cially in Asian populations. The Arg194Trp and Arg280His polymorphisms were not associated with overall glioma risk.
