MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation.The polycistronic miR-17-92 cluster is the first microRNA cluste...MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation.The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis.It has two other paralogs in the human genome,the miR-106b-25 cluster and the miR-106a-363 cluster.Collectively,the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families,namely the miR-17,the miR-92,the miR-18and the miR-19 families.Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma.Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses.Various targets of these microRNAs have been identified,and these targets are involved in tumor growth,cell survival and metastasis.In this review,we first describe the regulation of these clusters by c-Myc and E2F1,and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory loop.In addition,the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.展开更多
In recent years histone deacetylase inhibitors (HDACi’s) have emerged as promising therapeutics for cancer. While favorable responses to HDACi’s as single agents have been shown in several hematological malignancies...In recent years histone deacetylase inhibitors (HDACi’s) have emerged as promising therapeutics for cancer. While favorable responses to HDACi’s as single agents have been shown in several hematological malignancies, very little efficacy has been demonstrated in solid tumors. c-Myc (Myc), an oncoprotein commonly over-expressed in cancer, has been shown by several studies to play a critical role in HDACi-mediated cellular death. To expand upon these findings and determine the role that Myc plays in this process in solid tumors, we compared the effect of two HDAC inhibitors, SAHA and LAQ824, on the proliferation of solid tumor cell lines expressing high versus low levels of Myc. We found that cells expressing high levels of Myc were more sensitive to HDACi. In addition, there were significant differences in the type of response to HDACi treatment between the two cell types with prominent apoptosis in cells expressing higher levels of Myc while cell cycle arrest was more commonly observed in cells expressing lower levels of Myc. Interestingly, HDACi reduced the expression of Myc and one of its well-known oncogenic miRNA targets, miR-17~92 cluster, resulting in an increase in the expression of the master pro-apoptotic protein Bim. We propose that this novel mechanism may play a role in the potent anti-proliferative effects mediated by HDACi. Furthermore, these studies suggest that Myc expression could be used as a predictive biomarker to select patients with solid tumors who may be more responsive to HDACi treatment.展开更多
目的:采用Meta分析评估miR-17-92簇高表达在肿瘤患者预后中的价值。方法:检索Web of Science、Pub Med、EMBASE数据库从建库至2015年10月1日关于miR-17-92簇成员高表达与恶性肿瘤患者预后关系的英文文献,提取关键数据,计算合并风险比...目的:采用Meta分析评估miR-17-92簇高表达在肿瘤患者预后中的价值。方法:检索Web of Science、Pub Med、EMBASE数据库从建库至2015年10月1日关于miR-17-92簇成员高表达与恶性肿瘤患者预后关系的英文文献,提取关键数据,计算合并风险比(hazard ratio,HR)及其95%置信区间(confidence interval,CI)。结果:共纳入39篇文献,包含4 908例患者。miR-17-92簇的高表达与恶性肿瘤患者总生存率(HR=1.83,95%CI:1.58-2.12,P=0.000)低有关,并且miR-17-92簇高表达的肿瘤患者的无病生存率(HR=1.80,95%CI:1.43-2.26,P=0.000)、无进展生存率(HR=1.83,95%CI:1.11-3.02,P=0.018)及肿瘤特异性生存率(HR=1.59,95%CI:1.04-2.42,P=0.032)均降低;然而无复发生存率的合并风险比无统计学意义(P=0.539)。结论:miR-17-92簇高表达与恶性肿瘤患者的不良预后有关,有望成为新型肿瘤预后标志物。展开更多
文摘MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation.The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis.It has two other paralogs in the human genome,the miR-106b-25 cluster and the miR-106a-363 cluster.Collectively,the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families,namely the miR-17,the miR-92,the miR-18and the miR-19 families.Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma.Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses.Various targets of these microRNAs have been identified,and these targets are involved in tumor growth,cell survival and metastasis.In this review,we first describe the regulation of these clusters by c-Myc and E2F1,and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory loop.In addition,the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.
文摘In recent years histone deacetylase inhibitors (HDACi’s) have emerged as promising therapeutics for cancer. While favorable responses to HDACi’s as single agents have been shown in several hematological malignancies, very little efficacy has been demonstrated in solid tumors. c-Myc (Myc), an oncoprotein commonly over-expressed in cancer, has been shown by several studies to play a critical role in HDACi-mediated cellular death. To expand upon these findings and determine the role that Myc plays in this process in solid tumors, we compared the effect of two HDAC inhibitors, SAHA and LAQ824, on the proliferation of solid tumor cell lines expressing high versus low levels of Myc. We found that cells expressing high levels of Myc were more sensitive to HDACi. In addition, there were significant differences in the type of response to HDACi treatment between the two cell types with prominent apoptosis in cells expressing higher levels of Myc while cell cycle arrest was more commonly observed in cells expressing lower levels of Myc. Interestingly, HDACi reduced the expression of Myc and one of its well-known oncogenic miRNA targets, miR-17~92 cluster, resulting in an increase in the expression of the master pro-apoptotic protein Bim. We propose that this novel mechanism may play a role in the potent anti-proliferative effects mediated by HDACi. Furthermore, these studies suggest that Myc expression could be used as a predictive biomarker to select patients with solid tumors who may be more responsive to HDACi treatment.