生命学院2015秋季学术系列讲座 (之八)
报告人:Carlo M. Croce 院士
俄亥俄州立大学医学中心
题目:Causes and Consequences of microRNAs dysregulation in Cancer
时间:2015年11月4日(星期三),15:00pm
地点:BET体育365投注官网二楼大会议室(201)
主持人:赵云 教授
讲座提纲:
自从我们首次发现miR-15a 和miR-16基因在慢性淋巴细胞白血病中存在缺失,世界上许多实验室相继证明了miRNA在肺癌、乳腺癌、前列腺癌和胃肠道癌等肿瘤中表达异常。研究表明,多种分子机制,比如基因缺失、基因扩增、基因突变、转录调控的异常和表观遗传学的改变等,均可导致miRNA在肿瘤中的紊乱表达。
miRNA是通过调节特异性靶蛋白的表达,从而参与肿瘤的发生和发展过程。miRNA研究的挑战之一就是如何准确地鉴定miRNA的靶蛋白,并探索清楚它们参与肿瘤恶化的分子调控机制。miRNA研究的另一挑战就是鉴定不同肿瘤共有的异常信号途径所调控的miRNA。由于有些编码蛋白的癌基因和抑癌基因难以用药物进行干预,所以,我们可能通过干预其调控表达的下游miRNA,来达到干预肿瘤的发生和发展。如果这些miRNA对于肿瘤细胞的生长和存活非常重要,那么我们就可以采用miRNA和anti-miRNA,导致肿瘤的消退。目前,越来越多的研究采用深度测序技术,进行全基因组分析,探索肿瘤中miRNA基因及其拷贝数是否发生改变。这些研究成果,将为进一步揭示miRNA在肿瘤和其它疾病中的作用,提供更多有用的信息。
过去几年,肿瘤治疗的方向正在从传统的化疗模式,转向靶向性治疗模式。我们相信,随着研究的不断深入,miRNA和anti-miRNA将会有助于靶向治疗的药物开发。
Since the discovery of miR-15a and miR-16-1 deletions in CLL, many laboratories around the world have shown miRNA dysregulation in all tumors studied, including the most common, such as lung, breast, prostate and gastrointestinal cancers. Such dysregulation, like the dysregulation of oncogenes and tumor suppressor genes, can be caused by multiple mechanisms, such as deletion, amplification, mutation, transcriptional dysregulation and epigenetic changes.
As miRNAs have multiple targets, their function in tumorigenesis could be due to their regulation of a few specific targets, possibly even one, or many targets. A future challenge will be to identify all of the targets of the miRNAs involved in cancer and establish their contribution to malignant transformation. An additional challenge will be the identification of all of the miRNAs that are dysregulated by pathways that are consistently dysregulated in various types of human cancers. This point is of particular importance, as instead of focusing on specific alterations in protein-coding oncogenes or tumor suppressor genes — which may be difficult to treat — we could focus on their downstream miRNA targets. If these miRNA targets are crucial for the expression of the malignant phenotype and the cancer cells depend on their dysregulation for proliferation and survival, we can expect that the use of miRNAs or anti-miRNAs will result in tumor regression. Genomic analyses for alteration in miRNA genes or for copy number alterations in various human tumors by deep sequencing is in progress but has not been completed. These studies could provide additional information concerning the involvements of miRNAs in cancer and in many other diseases.
Over the past few years, we have observed a shift from conventional chemotherapy to targeted therapies, and miRNAs and anti-miRNAs will contribute extensively to the latter.
报告人简介:
卡洛·克罗齐(Carlo M. Croce)博士
美国俄亥俄州立大学杰出教授,
遗传研究所所长,分子病毒、免疫和医学遗传学系主任
美国国家科学院院士
美国国家艺术与科学院院士
美国国家医学院院士
美国癌症研究院首批一级院士
意大利国家科学院外籍院士
克罗齐教授在肿瘤致病机理研究做出了开创性的研究工作,揭示了许多在白血病、淋巴瘤及其他肿瘤中的突变基因,在世界上首次发现并鉴定BCL2基因、ALL1基因和TCL1基因。近年来,首次揭示微小RNA在肿瘤发生过程中的重要作用,掀起了微小RNA的研究热潮。在Science、Nature和Cell三大世界顶级期刊上发表文章近50篇,发表的论文产生了巨大影响,被广泛引用达到十几万次,H-index达到181,居于世界前列。克罗齐教授担任许多著名学术期刊如Cancer Research的主编和编委,并荣获许多著名的学术奖项,包括美国授予的乔奇癌症研究创新成就奖(Szent-Györgyi Prize for Progress in Cancer Research)、意大利总统授予的意大利国家金质奖章(Italian Gold Medal for Public Health)、欧洲癌症研究学会授予的Anthony Dipple Carcinogenesis Award、法国巴黎授予的Raymond Bourgine Award and Gold Medal of Paris等。现担任陈竺院士领导的上海交通大学国家转化医学中心的国际咨询委员会委员,与魏于全院士一起担任华西医院生物治疗国家重点实验室创办的英文期刊“Signal Transduction and Targeted Therapy”的主编。