国家自然基金申请书写作：ceRNA与肿瘤的发生发展

ceRNA对肿瘤的调控基于20多年对microRNA的相关研究，我们已了解到这类长度仅包含17-25个核苷酸的内源性非编码RNA作为转录后调控因子广泛参与机体的发育、分化以及新陈代谢等生理过程，其在生命周期的基因调控网络中发挥着重要的作用ADDINEN.CITEADDINEN.CITE.DATA\o"Alvarez-Garcia,2005#5"1,\o"Wang,2016#6"2。同时发现，microRNA在进化上高度保守，一种microRNA可通过与靶基因mRNA3’UTR区域的MRE识别并诱导基因沉默复合物RISC的装配，进而调控多个靶基因的活性或稳定性，且多种microRNA也可协同调控同一个靶基因。由此设想，共享有同一种microRNAMRE序列的不同基因转录物间构成了竞争，他们对同种microRNA的结合此消彼长，从而形成复杂的RNA调控网络，既调节各自的表达水平又相互影响，最终影响细胞的命运，即为ceRNA假说\o"Salmena,2011#7"ADDINEN.CITE<EndNote><Cite><Author>Salmena</Author><Year>2011</Year><RecNum>7</RecNum><DisplayText><styleface="superscript">3</style></DisplayText><record><rec-number>7</rec-number><foreign-keys><keyapp="EN"db-id="ssdftpwx8efex3edxa8v59st9552a5zwz9ee">7</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Salmena,L.</author><author>Poliseno,L.</author><author>Tay,Y.</author><author>Kats,L.</author><author>Pandolfi,P.P.</author></authors></contributors><auth-address>CancerGeneticsProgram,BethIsraelDeaconessCancerCenter,DepartmentsofMedicineandPathology,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA02215,USA.</auth-address><titles><title>AceRNAhypothesis:theRosettaStoneofahiddenRNAlanguage?</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>353-8</pages><volume>146</volume><number>3</number><edition>2011/08/02</edition><keywords><keyword>Animals</keyword><keyword>*GeneExpressionProfiling</keyword><keyword>GeneExpressionRegulation</keyword><keyword>Humans</keyword><keyword>MicroRNAs/genetics</keyword><keyword>Neoplasms/genetics/metabolism</keyword><keyword>Pseudogenes</keyword><keyword>RNA/*genetics/*metabolism</keyword><keyword>RNA,Messenger/genetics</keyword><keyword>RNA,Untranslated/genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug5</date></pub-dates></dates><isbn>1097-4172(Electronic) 0092-8674(Linking)</isbn><accession-num>21802130</accession-num><urls><related-urls><url>/pubmed/21802130</url></related-urls></urls><custom2>3235919</custom2><electronic-resource-num>10.1016/j.cell.2011.07.014 S0092-8674(11)00812-9[pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>3。其中，共享有相同MRE又构成竞争关系的不同转录物统称为竞争性内源RNA（completingendogenousRNA，ceRNA），包括编码蛋白的mRNA、长链非编码RNA（lncRNA）、假基因转录本以及环状RNA（circRNA）等\o"Tay,2014#8"ADDINEN.CITEADDINEN.CITE.DATA4。该假说先后通过生物信息学、细胞生物学等实验得到了验证，向我们展示了全新的转录组调控网络ADDINEN.CITEADDINEN.CITE.DATA\o"Tay,2011#9"5,\o"Poliseno,2010#10"6。普遍认为，精准的基因表达调控对机体的稳态维持和正常的生理活动至关重要，而RNAs调控网络的异常是诱发多种疾病的主要因素。ceRNA的提出进一步完善了人类对转录组和RNA调控网络的认知，为探究多种疾病的发生发展提供了全新的视野。研究表明，恶性肿瘤细胞中的ceRNAs能够与原癌基因、抑癌基因以及多种肿瘤相关信号通路因子的mRNA3’UTR区域的MRE竞争性结合靶向microRNA，从而促进或抑制microRNA的相关功能，在肿瘤的发生、恶化、侵袭、转移甚至药物治疗中发挥着重要作用\o"Karreth,2013#11"ADDINEN.CITEADDINEN.CITE.DATA7-10。例如通过对TCGA数据库中的恶性胶质瘤的基因表达谱分析发现，约有7000多种基因的转录物之间以ceRNA的方式相互联系和影响，其中涉及PTEN、视网膜母细胞瘤1（RB1）、VEGF-A、STAT3等肿瘤相关基因\o"Sumazin,2011#16"ADDINEN.CITE<EndNote><Cite><Author>Sumazin</Author><Year>2011</Year><RecNum>16</RecNum><DisplayText><styleface="superscript">11</style></DisplayText><record><rec-number>16</rec-number><foreign-keys><keyapp="EN"db-id="ssdftpwx8efex3edxa8v59st9552a5zwz9ee">16</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sumazin,P.</author><author>Yang,X.</author><author>Chiu,H.S.</author><author>Chung,W.J.</author><author>Iyer,A.</author><author>Llobet-Navas,D.</author><author>Rajbhandari,P.</author><author>Bansal,M.</author><author>Guarnieri,P.</author><author>Silva,J.</author><author>Califano,A.</author></authors></contributors><auth-address>ColumbiaInitiativeinSystemsBiology,ColumbiaUniversity,NewYork,NY10032,USA.</auth-address><titles><title>AnextensivemicroRNA-mediatednetworkofRNA-RNAinteractionsregulatesestablishedoncogenicpathwaysinglioblastoma</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>370-81</pages><volume>147</volume><number>2</number><edition>2011/10/18</edition><keywords><keyword>*GeneExpressionRegulation,Neoplastic</keyword><keyword>Glioblastoma/*genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>MicroRNAs/*metabolism</keyword><keyword>MultivariateAnalysis</keyword><keyword>Oncogenes</keyword><keyword>PTENPhosphohydrolase/genetics</keyword><keyword>RNAInterference</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct14</date></pub-dates></dates><isbn>1097-4172(Electronic) 0092-8674(Linking)</isbn><accession-num>22000015</accession-num><urls><related-urls><url>/pubmed/22000015</url></related-urls></urls><custom2>3214599</custom2><electronic-resource-num>10.1016/j.cell.2011.09.041 S0092-8674(11)01152-4[pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>11；Poliseno等发现，前列腺癌细胞中的假基因PTENP1转录本可通过竞争性结合miR-19b、miR-20a、miR-214等多种靶向PTEN的microRNA，提高PTEN的表达水平从而抑制PI3K/Akt信号通路的激活，最终抑制肿瘤细胞的增殖，相反，PTENP1表达的抑制伴随着PTEN表达的下调和肿瘤细胞增殖水平的提高\o"Poliseno,2010#10"ADDINEN.CITEADDINEN.CITE.DATA6；同样在肝癌相关的研究中发现，versicanmRNA的3’UTR竞争性结合miR-144、miR-133a等，且假基因OCT4-pg4的转录本可解除miR-145对OCT4的抑制，从而促进肿瘤细胞的增殖、迁移和侵袭能力，抑制细胞凋亡的发生ADDINEN.CITEADDINEN.CITE.DATA\o"Fang,2013#17"12,\o"Wang,2013#18"13。对肿瘤相关ceRNA研究的不断丰富和深入，不仅将有助于揭示和完善肿瘤发生和发展事件背后的分子机制，而且其可作为新型的生物标记分子和潜在的药物靶点用于肿瘤的临床诊治和预后评估ADDINEN.CITEADDINEN.CITE.DATA\o"Shao,2015#19"14,\o"Sanchez-Mejias,2015#20"15。参考文献ADDINEN.REFLIST1. 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