背景与目的:研究表明,环氧化酶-2(cyclooxygenase-2,COX-2)及信号转导和转录活化因子(signal transducers and activators of transcription,STAT)的活化均与肿瘤的发生、发展密切相关。本研究旨在检测COX-2、p-Stat3及p-Stat5在不同食...背景与目的:研究表明,环氧化酶-2(cyclooxygenase-2,COX-2)及信号转导和转录活化因子(signal transducers and activators of transcription,STAT)的活化均与肿瘤的发生、发展密切相关。本研究旨在检测COX-2、p-Stat3及p-Stat5在不同食管病变组织中的表达,并探讨三者在食管癌组织中表达的意义。方法:采用免疫组织化学SP法检测59例食管鳞状细胞癌、24例鳞状上皮非典型增生及18例正常鳞状上皮中COX-2、p-Stat3及p-Stat5的表达,并分析其与临床病理特征的关系。结果:COX-2在食管正常鳞状上皮、非典型增生和鳞状细胞癌的免疫组化染色平均积分分别为0.83±0.46、1.85±1.24和2.10±1.77,鳞状细胞癌与非典型增生组织的COX-2表达高于正常鳞状上皮,差异有统计学意义(P<0.05);在正常鳞状上皮、非典型增生及鳞状细胞癌中,p-Stat3的平均积分分别为0、0.76±0.59、2.83±1.27,p-Stat5分别为1.98±0.78、3.92±0.41、5.02±0.34,三种组织间两两比较,p-Stat3和p-Stat5表达的差异均有统计学意义(P<0.05)。食管鳞癌中淋巴结转移者及分化较低者COX-2表达低(P<0.05),且不同浸润深度的组织中p-Stat3表达的差异有统计学意义(P<0.05)。不同临床病理特征的组织中p-Stat5表达的差异无统计学意义(P>0.05)。COX-2、p-Stat3及p-Stat5三者的表达之间呈正相关。结论:COX-2可能在食管癌变早期具有重要作用,COX-2高表达可能是食管癌变过程中的早期事件。Stat3的磷酸化与食管癌的进展相关。展开更多
Objective:To investigate the neuroprotective effects of estradiol(E2)may be related to the interact with Grow Hormone(GH).Method:The protective effect of GH in different dose level(5,25,125,250,500 ng·mL-1)was ob...Objective:To investigate the neuroprotective effects of estradiol(E2)may be related to the interact with Grow Hormone(GH).Method:The protective effect of GH in different dose level(5,25,125,250,500 ng·mL-1)was observed in primary culture of rat hippocampal neurons for 24 hours through CCK-8 colorimetry.Phosphorylated-STAT5(P-STAT5)and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with different doses of GH(0.1~20 ng·mL-1),or different time of GH(15~90 min)to observe GH the optimal concentration and action time.SOCS2 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with different doses of E2(10-11~10-7 mol·L-1),or different time of E2(15~90 min)to observe E2 the optimal concentration and action time.P-STAT5 and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with GH(5 ng·mL-1),or E2(10-8 mol·L-1),or E2+GH.In this latter case E2 was added 60 min before GH.SOCS1,SOCS2 and SOCS3 mRNA and protein levels were detected in 24 h serum starved rat hippocampal neurons after 60 min treatment with E2(10-8 mol·L-1).SOCS2 mRNA and protein levels were detected in 24 h serum starved rat hippocampal neurons after 60 min treatment with GH(5 ng·mL-1),or E2(10-8 mol·L-1),or E2+GH.In this latter case E2 was added 60 min before GH.Result:It was testified that GH was nontoxic to rat hippocampal neurons in the range of 5~250 ng·mL-1.However,if GH concentration was over 250 ng·mL-1,the activity of hippocampal neurons began to decrease.STAT5 and P-STAT5 protein levels were response to increasing concentrations of GH(0.1~20 ng·mL-1)in rat hippocampal neurons after 60 min of treatment,which determined optimal concentration and effect time of GH.SOCS2 protein levels were response to increasing concentrations of E2(10-11~10-7 mol·L-1)in rat hippocampal neurons after 60 min of treatment,which determined optimal concentration and effect time of E2.P-STAT5 and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 60 min GH(5 ng·mL-1)or E2(10-8 mol·L-1)treatment.For the combined treatment with the two hormones,E2 pretreatment(10-8 mol·L-1)60 min before GH induced a significant increase of P-STAT5 and STAT5 compared with GH alone.Treatment for 60 min with E2(10-8 mol·L-1)did not modify neither protein levels nor RNAs of SOCS1 and SOCS3 in rat hippocampal neurons,while E2 significantly reduced SOCS2 protein level without affecting its mRNA level.Neither 60 min treatment with GH(5 ng·mL-1)or E2(10-8 mol·L-1)nor the combined treatment with the two hormones induced any modifi cation of SOCS2 mRNA,whereas E2 pretreatment 60 min before GH was able to induce a signifi cant reduction of SOCS2 protein levels.Conclusion:E2 amplifies intracellular GH signaling by favoring SOCS2 degradation through the proteasome machinery.展开更多
C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, w...C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for CML therapy. Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for CML therapy that takes advantage of natural products.展开更多
文摘背景与目的:研究表明,环氧化酶-2(cyclooxygenase-2,COX-2)及信号转导和转录活化因子(signal transducers and activators of transcription,STAT)的活化均与肿瘤的发生、发展密切相关。本研究旨在检测COX-2、p-Stat3及p-Stat5在不同食管病变组织中的表达,并探讨三者在食管癌组织中表达的意义。方法:采用免疫组织化学SP法检测59例食管鳞状细胞癌、24例鳞状上皮非典型增生及18例正常鳞状上皮中COX-2、p-Stat3及p-Stat5的表达,并分析其与临床病理特征的关系。结果:COX-2在食管正常鳞状上皮、非典型增生和鳞状细胞癌的免疫组化染色平均积分分别为0.83±0.46、1.85±1.24和2.10±1.77,鳞状细胞癌与非典型增生组织的COX-2表达高于正常鳞状上皮,差异有统计学意义(P<0.05);在正常鳞状上皮、非典型增生及鳞状细胞癌中,p-Stat3的平均积分分别为0、0.76±0.59、2.83±1.27,p-Stat5分别为1.98±0.78、3.92±0.41、5.02±0.34,三种组织间两两比较,p-Stat3和p-Stat5表达的差异均有统计学意义(P<0.05)。食管鳞癌中淋巴结转移者及分化较低者COX-2表达低(P<0.05),且不同浸润深度的组织中p-Stat3表达的差异有统计学意义(P<0.05)。不同临床病理特征的组织中p-Stat5表达的差异无统计学意义(P>0.05)。COX-2、p-Stat3及p-Stat5三者的表达之间呈正相关。结论:COX-2可能在食管癌变早期具有重要作用,COX-2高表达可能是食管癌变过程中的早期事件。Stat3的磷酸化与食管癌的进展相关。
文摘Objective:To investigate the neuroprotective effects of estradiol(E2)may be related to the interact with Grow Hormone(GH).Method:The protective effect of GH in different dose level(5,25,125,250,500 ng·mL-1)was observed in primary culture of rat hippocampal neurons for 24 hours through CCK-8 colorimetry.Phosphorylated-STAT5(P-STAT5)and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with different doses of GH(0.1~20 ng·mL-1),or different time of GH(15~90 min)to observe GH the optimal concentration and action time.SOCS2 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with different doses of E2(10-11~10-7 mol·L-1),or different time of E2(15~90 min)to observe E2 the optimal concentration and action time.P-STAT5 and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 24 h of serum starvation and treated for 60 min with GH(5 ng·mL-1),or E2(10-8 mol·L-1),or E2+GH.In this latter case E2 was added 60 min before GH.SOCS1,SOCS2 and SOCS3 mRNA and protein levels were detected in 24 h serum starved rat hippocampal neurons after 60 min treatment with E2(10-8 mol·L-1).SOCS2 mRNA and protein levels were detected in 24 h serum starved rat hippocampal neurons after 60 min treatment with GH(5 ng·mL-1),or E2(10-8 mol·L-1),or E2+GH.In this latter case E2 was added 60 min before GH.Result:It was testified that GH was nontoxic to rat hippocampal neurons in the range of 5~250 ng·mL-1.However,if GH concentration was over 250 ng·mL-1,the activity of hippocampal neurons began to decrease.STAT5 and P-STAT5 protein levels were response to increasing concentrations of GH(0.1~20 ng·mL-1)in rat hippocampal neurons after 60 min of treatment,which determined optimal concentration and effect time of GH.SOCS2 protein levels were response to increasing concentrations of E2(10-11~10-7 mol·L-1)in rat hippocampal neurons after 60 min of treatment,which determined optimal concentration and effect time of E2.P-STAT5 and STAT5 protein levels were tested in primary culture of rat hippocampal neurons after 60 min GH(5 ng·mL-1)or E2(10-8 mol·L-1)treatment.For the combined treatment with the two hormones,E2 pretreatment(10-8 mol·L-1)60 min before GH induced a significant increase of P-STAT5 and STAT5 compared with GH alone.Treatment for 60 min with E2(10-8 mol·L-1)did not modify neither protein levels nor RNAs of SOCS1 and SOCS3 in rat hippocampal neurons,while E2 significantly reduced SOCS2 protein level without affecting its mRNA level.Neither 60 min treatment with GH(5 ng·mL-1)or E2(10-8 mol·L-1)nor the combined treatment with the two hormones induced any modifi cation of SOCS2 mRNA,whereas E2 pretreatment 60 min before GH was able to induce a signifi cant reduction of SOCS2 protein levels.Conclusion:E2 amplifies intracellular GH signaling by favoring SOCS2 degradation through the proteasome machinery.
基金supported by the National Natural Science Foundation of China (31471223, 31230042, 31771459, 31770879)the Project of Science and Technology of Guangzhou (201504010022)the National Key R&D Program of China (2017YFA0504400) from the Ministry of Science and Technology of China
文摘C-Myc and signal transducer and activator of transcription(STAT) family proteins have been proposed to be important downstream genes of BCR-ABL, which characterizes most cases of chronic myeloid leukemia(CML). Here, we report a c-Myc pathway-targeted screening of seven natural anticancer compounds, in which we identified cryptotanshinone as a highly promising agent for CML therapy. Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability of K562 cells correlated with p-STAT5 suppression. Unexpectedly, imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells. We demonstrated that cryptotanshinone, as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance. Moreover, we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance(MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR. Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR. These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3, providing a new strategy for CML therapy that takes advantage of natural products.
