Background Human epidermal growth factor 2 （HER2） is one of the most important prediction factors, but only 25%-30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular marker...Background Human epidermal growth factor 2 （HER2） is one of the most important prediction factors, but only 25%-30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients.This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients. Methods Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis. Results Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods （P=0.047 and P=-0.05, respectively）. Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index （kappa=0.37）, allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69-2.74 fold. Conclusions Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients.展开更多
Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we sho...Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we showed that zebrafish cdk1^(-/-)embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry,M phase progression,and cell differentiation but not in interkinetic nuclear migration.We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis.While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells,the depletion of cyclin B1 led to M phase arrest.Moreover,phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2mutants,but not in ccnb1 mutants.Furthermore,overexpression of TOP2A^(S1213D),the phosphomimetic form of human TOP2A,rescued S phase entry and alleviated the microphthalmia defects in both cdk1^(-/-)and ccna2^(-/-)embryos.Taken together,our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression.展开更多
目的探讨miRNA-381通过改变细胞周期蛋白A2(CCNA2)的表达水平,对乳腺癌增殖、迁移和预后的影响。方法选择2017年6月至2018年6月于上海市静安区中心医院接受手术治疗的乳腺癌患者血清标本122例作为乳腺癌组。选择同期体检健康者血清标本7...目的探讨miRNA-381通过改变细胞周期蛋白A2(CCNA2)的表达水平,对乳腺癌增殖、迁移和预后的影响。方法选择2017年6月至2018年6月于上海市静安区中心医院接受手术治疗的乳腺癌患者血清标本122例作为乳腺癌组。选择同期体检健康者血清标本75例作为对照组。采用实时荧光定量PCR(RT-PCR)检测各组血清和乳腺癌细胞系中miRNA-381和CCNA2的表达水平。结果乳腺癌组血清miRNA-381的表达水平明显低于对照组(1.71±0.64 vs 2.66±0.89,t=8.693,P<0.01),术后乳腺癌患者血清miRNA-381的表达水平较术前(2.46±0.76 vs 1.71±0.64,t=8.338,P<0.01)明显升高;而乳腺癌组血清CCNA2的表达水平较对照组(2.91±0.95 vs 2.33±0.73,t=4.528,P<0.01)明显升高,术后血清CCNA2的表达水平(2.42±0.63 vs 2.91±0.95,t=4.748,P<0.01)较术前明显降低。miRNA-381抑制乳腺癌细胞CCNA2基因和蛋白质的表达(P<0.01),且对乳腺癌细胞的增殖和迁移具有明显的抑制作用(P<0.01)。乳腺癌患者血清miRNA-381和CCNA2的表达水平在淋巴结转移与否、TNM分期和Ki67比率之间的差异具有统计学意义(P<0.01)。与死亡组比较,生存组血清miRNA-381的表达水平明显升高(P<0.01),而血清CCNA2的表达水平明显降低。血清miRNA-381和CCNA2的表达在预测乳腺癌患者术后3年内出现死亡时具有较高的预测效能,二者联合检测的敏感性为75.0%,特异性为84.7%,AUC^(ROC)为0.876,均显著高于miRNA-381(Z=1.993,P<0.05)和CCNA2(Z=2.539,P<0.05)单独检测。结论miRNA-381通过改变CCNA2的表达,影响乳腺癌细胞的增殖和迁移,血清miRNA-381和CCNA2在预测乳腺癌预后方面具有重要临床意义。展开更多
基金This project was supported by the grants from the National Natural Science Foundation of China （No. 30672424 and No. 30471684）.Acknowledgements： We thank DU Cai and WANG Li-na for their laboratory and computer support, LU Jing-qiao and ZHAO Jian-qing for data analysis, and Professors HUNG Mien-chie and Stephanie Ann Miller for paper comments.
文摘Background Human epidermal growth factor 2 （HER2） is one of the most important prediction factors, but only 25%-30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients.This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients. Methods Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis. Results Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods （P=0.047 and P=-0.05, respectively）. Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index （kappa=0.37）, allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69-2.74 fold. Conclusions Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients.
基金supported by grants from the National Key Research and Development Program of China (2017YFA0104600)the National Natural Science Foundation of China (31970767, 31771597 and 31571515)+1 种基金the National Basic Research Program of China (973 Program 2012CB966601 and 2013CB945300)the Ministry of Science and Technology of the People’s Republic of China (2011DFB30010)。
文摘Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we showed that zebrafish cdk1^(-/-)embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry,M phase progression,and cell differentiation but not in interkinetic nuclear migration.We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis.While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells,the depletion of cyclin B1 led to M phase arrest.Moreover,phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2mutants,but not in ccnb1 mutants.Furthermore,overexpression of TOP2A^(S1213D),the phosphomimetic form of human TOP2A,rescued S phase entry and alleviated the microphthalmia defects in both cdk1^(-/-)and ccna2^(-/-)embryos.Taken together,our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression.
文摘目的探讨miRNA-381通过改变细胞周期蛋白A2(CCNA2)的表达水平,对乳腺癌增殖、迁移和预后的影响。方法选择2017年6月至2018年6月于上海市静安区中心医院接受手术治疗的乳腺癌患者血清标本122例作为乳腺癌组。选择同期体检健康者血清标本75例作为对照组。采用实时荧光定量PCR(RT-PCR)检测各组血清和乳腺癌细胞系中miRNA-381和CCNA2的表达水平。结果乳腺癌组血清miRNA-381的表达水平明显低于对照组(1.71±0.64 vs 2.66±0.89,t=8.693,P<0.01),术后乳腺癌患者血清miRNA-381的表达水平较术前(2.46±0.76 vs 1.71±0.64,t=8.338,P<0.01)明显升高;而乳腺癌组血清CCNA2的表达水平较对照组(2.91±0.95 vs 2.33±0.73,t=4.528,P<0.01)明显升高,术后血清CCNA2的表达水平(2.42±0.63 vs 2.91±0.95,t=4.748,P<0.01)较术前明显降低。miRNA-381抑制乳腺癌细胞CCNA2基因和蛋白质的表达(P<0.01),且对乳腺癌细胞的增殖和迁移具有明显的抑制作用(P<0.01)。乳腺癌患者血清miRNA-381和CCNA2的表达水平在淋巴结转移与否、TNM分期和Ki67比率之间的差异具有统计学意义(P<0.01)。与死亡组比较,生存组血清miRNA-381的表达水平明显升高(P<0.01),而血清CCNA2的表达水平明显降低。血清miRNA-381和CCNA2的表达在预测乳腺癌患者术后3年内出现死亡时具有较高的预测效能,二者联合检测的敏感性为75.0%,特异性为84.7%,AUC^(ROC)为0.876,均显著高于miRNA-381(Z=1.993,P<0.05)和CCNA2(Z=2.539,P<0.05)单独检测。结论miRNA-381通过改变CCNA2的表达,影响乳腺癌细胞的增殖和迁移,血清miRNA-381和CCNA2在预测乳腺癌预后方面具有重要临床意义。
