Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzuma...Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data. Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.展开更多
文摘目的探讨溃疡性结肠炎(UC)血小板中钾通道和NLRP3的表达,以及与UC临床特征的关联分析。方法收集11例正常对照组和17例UC患者临床资料。提取血小板,采用RT-PCR、Western blot法检测Kca3.1、Kv1.3及NLRP3的表达水平。结果与正常对照组相比,UC患者血小板中Kca3.1、Kv1.3及NLRP3 m RNA表达量均明显增加(t=-6.067、-4.991、-18.981,P<0.05),与UC严重程度无明显相关。UC患者血小板中Kca3.1、Kv1.3及NLRP3蛋白表达量均明显高于对照组,差异有统计学意义(t=-9.627、-7.39、-7.821,P<0.05),与UC严重程度无明显相关。UC患者血小板中Kca3.1与NLRP3蛋白表达水平明显相关(r=0.877,P<0.05),Kv1.3与NLRP3蛋白表达水平有一定的相关性,但差异无统计学意义。UC患者血小板中Kca3.1、Kv1.3及NLRP3蛋白表达与患者临床指标红细胞沉降率、C反应蛋白及Mayo评分均不相关。结论 UC患者血小板中NLRP3与钾通道表达增高,两者具有一定相关。
基金Department of Defense Breast Cancer Research Program(BC142323)the Margaret E.Early Medical Research Trust for experiment design,collection,analysis,and interpretation of data,and writing of the manuscript
文摘Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data. Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.
