lncRNA-在肿瘤中的作用

lncRNA在肿瘤中的作用长链非编码RNA(longnon-codingRNA,lncRNA)是一类转录本长度超过200nt、不编码蛋白的RNA，这类RNA起初被认为是基因组转录的“噪音”，随着2007年Hotair功能的被发掘，lncRNA的功能渐渐明晰。据计算，约有93%的转录本为lncRNA\o"Ponting,2009#19"ADDINEN.CITE<EndNote><Cite><Author>Ponting</Author><Year>2009</Year><RecNum>19</RecNum><DisplayText><styleface="superscript">1</style></DisplayText><record><rec-number>19</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">19</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ponting,ChrisP</author><author>Oliver,PeterL</author><author>Reik,Wolf</author></authors></contributors><titles><title>EvolutionandfunctionsoflongnoncodingRNAs</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>629-641</pages><volume>136</volume><number>4</number><dates><year>2009</year></dates><isbn>0092-8674</isbn><urls></urls></record></Cite></EndNote>1，lncRNA通常位于细胞核和细胞质。但是lncRNA的基因转录水平一般低于蛋白质编码基因，序列保守性差，承受的进化压力小，但promoter序列通常比较保守。lncRNA与小分子RNA相比，序列更长、空间结构也较为复杂，参与表达调控的机制也更具有多样性和复杂性。尽管目前只有一小部分lncRNA的功能有相关报道，但可以明确的是lncRNA参与发育、分化、代谢等多方面的调控。lncRNA在癌症中显示出多种生物学功能：包括表观遗传调控、DNA损伤和细胞周期调控、对microRNA的调控、参与信号转导通路和介导激素导致的癌症\o"Sahu,2015#20"ADDINEN.CITE<EndNote><Cite><Author>Sahu</Author><Year>2015</Year><RecNum>20</RecNum><DisplayText><styleface="superscript">2</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">20</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sahu,Anirban</author><author>Singhal,Udit</author><author>Chinnaiyan,ArulM</author></authors></contributors><titles><title>LongnoncodingRNAsincancer:fromfunctiontotranslation</title><secondary-title>TrendsinCancer</secondary-title></titles><periodical><full-title>TrendsinCancer</full-title></periodical><pages>93-109</pages><volume>1</volume><number>2</number><dates><year>2015</year></dates><isbn>2405-8033</isbn><urls></urls></record></Cite></EndNote>2。在癌症中，lncRNA可以作为癌基因和抑癌基因的转录调控分子\o"Prensner,2011#21"ADDINEN.CITE<EndNote><Cite><Author>Prensner</Author><Year>2011</Year><RecNum>21</RecNum><DisplayText><styleface="superscript">3</style></DisplayText><record><rec-number>21</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">21</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Prensner,JohnR</author><author>Chinnaiyan,ArulM</author></authors></contributors><titles><title>TheemergenceoflncRNAsincancerbiology</title><secondary-title>Cancerdiscovery</secondary-title></titles><periodical><full-title>Cancerdiscovery</full-title></periodical><pages>391-407</pages><volume>1</volume><number>5</number><dates><year>2011</year></dates><isbn>2159-8274</isbn><urls></urls></record></Cite></EndNote>3。比如过表达的HOTAIRlncRNA与恶性乳腺癌\o"Gupta,2010#22"ADDINEN.CITE<EndNote><Cite><Author>Gupta</Author><Year>2010</Year><RecNum>22</RecNum><DisplayText><styleface="superscript">4</style></DisplayText><record><rec-number>22</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">22</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Gupta,RajnishA</author><author>Shah,Nilay</author><author>Wang,KevinC</author><author>Kim,Jeewon</author><author>Horlings,HugoM</author><author>Wong,DavidJ</author><author>Tsai,Miao-Chih</author><author>Hung,Tiffany</author><author>Argani,Pedram</author><author>Rinn,JohnL</author></authors></contributors><titles><title>Longnon-codingRNAHOTAIRreprogramschromatinstatetopromotecancermetastasis</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>1071-1076</pages><volume>464</volume><number>7291</number><dates><year>2010</year></dates><isbn>0028-0836</isbn><urls></urls></record></Cite></EndNote>4、结肠癌\o"Kogo,2011#23"ADDINEN.CITE<EndNote><Cite><Author>Kogo</Author><Year>2011</Year><RecNum>23</RecNum><DisplayText><styleface="superscript">5</style></DisplayText><record><rec-number>23</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">23</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Kogo,Ryunosuke</author><author>Shimamura,Teppei</author><author>Mimori,Koshi</author><author>Kawahara,Kohichi</author><author>Imoto,Seiya</author><author>Sudo,Tomoya</author><author>Tanaka,Fumiaki</author><author>Shibata,Kohei</author><author>Suzuki,Akira</author><author>Komune,Shizuo</author></authors></contributors><titles><title>LongnoncodingRNAHOTAIRregulatespolycomb-dependentchromatinmodificationandisassociatedwithpoorprognosisincolorectalcancers</title><secondary-title>Cancerresearch</secondary-title></titles><periodical><full-title>Cancerresearch</full-title></periodical><pages>6320-6326</pages><volume>71</volume><number>20</number><dates><year>2011</year></dates><isbn>0008-5472</isbn><urls></urls></record></Cite></EndNote>5、肝癌\o"Yang,2011#24"ADDINEN.CITE<EndNote><Cite><Author>Yang</Author><Year>2011</Year><RecNum>24</RecNum><DisplayText><styleface="superscript">6</style></DisplayText><record><rec-number>24</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">24</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yang,Zhe</author><author>Zhou,Lin</author><author>Wu,Li-Ming</author><author>Lai,Ming-Chun</author><author>Xie,Hai-Yang</author><author>Zhang,Feng</author><author>Zheng,Shu-Sen</author></authors></contributors><titles><title>Overexpressionoflongnon-codingRNAHOTAIRpredictstumorrecurrenceinhepatocellularcarcinomapatientsfollowinglivertransplantation</title><secondary-title>Annalsofsurgicaloncology</secondary-title></titles><periodical><full-title>Annalsofsurgicaloncology</full-title></periodical><pages>1243-1250</pages><volume>18</volume><number>5</number><dates><year>2011</year></dates><isbn>1068-9265</isbn><urls></urls></record></Cite></EndNote>6和胃肠道间质瘤\o"Niinuma,2012#25"ADDINEN.CITE<EndNote><Cite><Author>Niinuma</Author><Year>2012</Year><RecNum>25</RecNum><DisplayText><styleface="superscript">7</style></DisplayText><record><rec-number>25</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">25</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Niinuma,Takeshi</author><author>Suzuki,Hiromu</author><author>Nojima,Masanori</author><author>Nosho,Katsuhiko</author><author>Yamamoto,Hiroyuki</author><author>Takamaru,Hiroyuki</author><author>Yamamoto,Eiichiro</author><author>Maruyama,Reo</author><author>Nobuoka,Takayuki</author><author>Miyazaki,Yasuaki</author></authors></contributors><titles><title>UpregulationofmiR-196aandHOTAIRdrivemalignantcharacteringastrointestinalstromaltumors</title><secondary-title>Cancerresearch</secondary-title></titles><periodical><full-title>Cancerresearch</full-title></periodical><pages>1126-1136</pages><volume>72</volume><number>5</number><dates><year>2012</year></dates><isbn>0008-5472</isbn><urls></urls></record></Cite></EndNote>7有关。而lncRNATARID可以预防癌症形成，通过甲基化抑癌基因的表达\o"Arab,2014#26"ADDINEN.CITE<EndNote><Cite><Author>Arab</Author><Year>2014</Year><RecNum>26</RecNum><DisplayText><styleface="superscript">8</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">26</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Arab,Khelifa</author><author>Park,YoonJung</author><author>Lindroth,AndersM</author><author>Schäfer,Andrea</author><author>Oakes,Christopher</author><author>Weichenhan,Dieter</author><author>Lukanova,Annekatrin</author><author>Lundin,Eva</author><author>Risch,Angela</author><author>Meister,Michael</author></authors></contributors><titles><title>LongnoncodingRNATARIDdirectsdemethylationandactivationofthetumorsuppressorTCF21viaGADD45A</title><secondary-title>Molecularcell</secondary-title></titles><periodical><full-title>Molecularcell</full-title></periodical><pages>604-614</pages><volume>55</volume><number>4</number><dates><year>2014</year></dates><isbn>1097-2765</isbn><urls></urls></record></Cite></EndNote>8。表观遗传调控表观遗传是指遗传表型和基因表达发生了可遗传的改变，而不涉及DNA序列的变化，主要包括DNA甲基化、组蛋白修饰和染色质重塑等修饰形式。近年来研究表明，lncRNAs通过表观遗传调控介导癌症发生中起到至关重要的作用。lncRNAs能够通过表观遗传调控、转录调控以及转录后调控等多个层面调节基因的表达，从而参与癌症中细胞增殖、分化和凋亡等多种生物学过程\o"Sharma,2010#27"ADDINEN.CITE<EndNote><Cite><Author>Sharma</Author><Year>2010</Year><RecNum>27</RecNum><DisplayText><styleface="superscript">9</style></DisplayText><record><rec-number>27</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">27</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sharma,Shikhar</author><author>Kelly,TheresaK</author><author>Jones,PeterA</author></authors></contributors><titles><title>Epigeneticsincancer</title><secondary-title>Carcinogenesis</secondary-title></titles><periodical><full-title>Carcinogenesis</full-title></periodical><pages>27-36</pages><volume>31</volume><number>1</number><dates><year>2010</year></dates><isbn>0143-3334</isbn><urls></urls></record></Cite></EndNote>9。在癌症发展过程中，lncRNAs参与了多种表观遗传复合物的调节过程，从而抑制或激活基因的表达。例如，lncRNAs可以与多梳蛋白复合体结合来调控癌症发生\o"Gupta,2010#22"ADDINEN.CITE<EndNote><Cite><Author>Gupta</Author><Year>2010</Year><RecNum>22</RecNum><DisplayText><styleface="superscript">4</style></DisplayText><record><rec-number>22</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">22</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Gupta,RajnishA</author><author>Shah,Nilay</author><author>Wang,KevinC</author><author>Kim,Jeewon</author><author>Horlings,HugoM</author><author>Wong,DavidJ</author><author>Tsai,Miao-Chih</author><author>Hung,Tiffany</author><author>Argani,Pedram</author><author>Rinn,JohnL</author></authors></contributors><titles><title>Longnon-codingRNAHOTAIRreprogramschromatinstatetopromotecancermetastasis</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>1071-1076</pages><volume>464</volume><number>7291</number><dates><year>2010</year></dates><isbn>0028-0836</isbn><urls></urls></record></Cite></EndNote>4。PRC1和2是已知的致癌基因，能够导致许多恶性肿瘤的发生。FAL1lncRNA与PRC1的亚基BMI1结合。在卵巢癌,FAL1被证明可以加快癌症的进展和缩短病人的生存时间。FAL1与BMI1结合可阻止BMI1降解以稳定PRC1复合物，这可使PRC1占据和抑制p21等目标基因的启动子,导致细胞周期失调和增加肿瘤发生的机会\o"Puvvula,2014#28"ADDINEN.CITE<EndNote><Cite><Author>Puvvula</Author><Year>2014</Year><RecNum>28</RecNum><DisplayText><styleface="superscript">10</style></DisplayText><record><rec-number>28</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">28</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Puvvula,PavanKumar</author><author>Desetty,RohiniDevi</author><author>Pineau,Pascal</author><author>Marchio,Agnés</author><author>Moon,Anne</author><author>Dejean,Anne</author><author>Bischof,Oliver</author></authors></contributors><titles><title>LongnoncodingRNAPANDAandscaffold-attachment-factorSAFAcontrolsenescenceentryandexit</title><secondary-title>Naturecommunications</secondary-title></titles><periodical><full-title>Naturecommunications</full-title></periodical><volume>5</volume><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>10。除了PRC复合物,lncRNAs还与SWI/SNF染色质重塑复合物有关，SWI/SNF是一类重要的依赖ATP的染色质重塑复合物,能够改变核小体的高级折叠结构，干扰组蛋白与DNA结合，暴露启动子序列的结合位点，使转录因子能与特异性启动子序列结合，从而激活基因转录\o"Prensner,2013#29"ADDINEN.CITEADDINEN.CITE.DATA11-14。在癌症中,SWI/SNF染色质重塑复合物被广泛认为是一种肿瘤抑制分子，因为有害突变出现在大约20%的癌症中\o"Reisman,2009#33"ADDINEN.CITE<EndNote><Cite><Author>Reisman</Author><Year>2009</Year><RecNum>33</RecNum><DisplayText><styleface="superscript">15</style></DisplayText><record><rec-number>33</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">33</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Reisman,D</author><author>Glaros,S</author><author>Thompson,EA</author></authors></contributors><titles><title>TheSWI/SNFcomplexandcancer</title><secondary-title>Oncogene</secondary-title></titles><periodical><full-title>Oncogene</full-title></periodical><pages>1653-1668</pages><volume>28</volume><number>14</number><dates><year>2009</year></dates><isbn>0950-9232</isbn><urls></urls></record></Cite></EndNote>15。LncTCF7在肝癌细胞(HCC)高表达，在肝癌干细胞的自我更新能力的维护中起重要作用\o"Wang,2015#34"ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2015</Year><RecNum>34</RecNum><DisplayText><styleface="superscript">12</style></DisplayText><record><rec-number>34</rec-number><foreign-keys><keyapp="EN"db-id="9sf2daeww0wedaevdp85dftp0zss5p2xdxs0">34</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,Yanying</author><author>He,Lei</author><author>Du,Ying</author><author>Zhu,Pingping</author><author>Huang,Guanling</author><author>Luo,Jianjun</author><author>Yan,Xinlong</author><author>Ye,Buqing</author><author>Li,Chong</author><author>Xia,Pengyan</author></authors></contributors><titles><title>TheLongNoncodingRNAlncTCF7PromotesSelf-RenewalofHumanLiverCancerStemCellsthroughActivationofWntSignaling</title><secondary-title>Cellstemcell</secondary-title></titles><periodical><full-title>Cellstemcell</full-title></periodical><pages>413-425</pages><volume>16</volume><number>4</number><dates><year>2015</year></dates><isbn>1934-5909</isbn><urls></urls></record></Cite></EndNote>12。LncTCF7可以激活Wnt信号通路，通过结合和募集SWI/SNF复合物来与TCF7基因的启动子结合激活基因的表达，这导致了肝癌肿瘤的发生。除此以外，lncRNAs还可以参与由DNA甲基化、乙酰化等介导的基因转录过程来调控肿瘤发生过程。DNA损伤和细胞周期调控lncRNAs广泛参与DNA损伤修复、细胞周期调控等生理或病理过程调控肿瘤的发生发展。对DNA损伤进行修复和细胞周期检查点的适当调节对于维持细胞的完整性识有明显的增长，但这只是冰山一角，lncRNAs在癌症中行使的复杂生物学功能，其详细的调控机制仍有待深入研究。参考文献ADDINEN.REFLIST1. PontingCP,OliverPL,ReikW.EvolutionandfunctionsoflongnoncodingRNAs.Cell.2009;136(4):629-41.2. SahuA,SinghalU,ChinnaiyanAM.LongnoncodingRNAsincancer:fromfunctiontotranslation.TrendsinCancer.2015;1(2):93-109.3. PrensnerJR,ChinnaiyanAM.TheemergenceoflncRNAsincancerbiology.Cancerdiscovery.2011;1(5):391-407.4. GuptaRA,ShahN,WangKC,KimJ,HorlingsHM,WongDJ,etal.Longnon-codingRNAHOTAIRreprogramschromatinstatetopromotecancermetastasis.Nature.2010;464(7291):1071-6.5. KogoR,ShimamuraT,MimoriK,KawaharaK,ImotoS,SudoT,etal.LongnoncodingRNAHOTAIRregulatespolycomb-dependentchromatinmodificationandisassociatedwithpoorprognosisincolorectalcancers.Cancerresearch.2011;71(20):6320-6.6. YangZ,ZhouL,WuL-M,LaiM-C,XieH-Y,ZhangF,etal.Overexpressionoflongnon-codingRNAHOTAIRpredictstumorrecurrenceinhepatocellularcarcinomapatientsfollowinglivertransplantation.Annalsofsurgicaloncology.2011;18(5):1243-50.7. NiinumaT,SuzukiH,NojimaM,NoshoK,YamamotoH,TakamaruH,etal.UpregulationofmiR-196aandHOTAIRdrivemalignantcharacteringastrointestinalstromaltumors.Cancerresearch.2012;72(5):1126-36.8. ArabK,ParkYJ,LindrothAM,SchäferA,OakesC,WeichenhanD,etal.LongnoncodingRNATARIDdirectsdemethylationandactivationofthetumorsuppressorTCF21viaGADD45A.Molecularcell.2014;55(4):604-14.9. SharmaS,KellyTK,JonesPA.Epigeneticsincancer.Carcinogenesis.2010;31(1):27-36.10. PuvvulaPK,DesettyRD,PineauP,MarchioA,MoonA,DejeanA,etal.LongnoncodingRNAPANDAandscaffold-attachment-factorSAFAcontrolsenescenceentryandexit.Naturecommunications.2014;5.11. PrensnerJR,IyerMK,SahuA,AsanganiIA,CaoQ,PatelL,etal.ThelongnoncodingRNASChLAP1promotesaggressiveprostatecancerandantagonizestheSWI/SNFcomplex.Naturegenetics.2013;45(11):1392-8.12. WangY,HeL,DuY,ZhuP,HuangG,LuoJ,etal.TheLongNoncodingRNAlncTCF7PromotesSelf-RenewalofHumanLiverCancerStemCellsthroughActivationofWntSignaling.Cellstemcell.2015;16(4):413-25.13. ZhuY,RowleyMJ,BöhmdorferG,WierzbickiAT.ASWI/SNFchromatin-remodelingcomplexactsinnoncodingRNA-mediatedtranscriptionalsilencing.Molecularcell.2013;49(2):298-309.14. HanP,LiW,LinC-H,YangJ,ShangC,NuernbergST,etal.AlongnoncodingRNAprotectstheheartfrompathologicalhypertrophy.Nature.2014.15. ReismanD,GlarosS,ThompsonE.TheSWI/SNFcomplexandcancer.Oncogene.2009;28(14):1653-68.16. MullerPA,VousdenKH.p53mutationsincancer.Naturecellbiology.2013;15(1):2-8.17. VazquezA,BondEE,LevineAJ,BondGL.Thegeneticsofthep53pathway,apoptosisandcancertherapy.NaturereviewsDrugdiscovery.2008;7(12):979-87.18. DimitrovaN,ZamudioJR,JongRM,SoukupD,ResnickR,SarmaK,etal.LincRNA-p21activatesp21incistopromotePolycombtargetgeneexpressionandtoenforcetheG1/Scheckpoint.Molecularcell.2014;54(5):777-90.19. LiuX,LiD,ZhangW,GuoM,ZhanQ.Longnon‐codingRNAgadd7interactswithTDP‐43andregulatesCdk6mRNAdecay.TheEMBOjournal.2012;31(23):4415-27.20. IorioMV,CroceCM.MicroRNAdysregulationincancer:diagnostics,monitoringandtherapeutics.Acomprehensivereview.EMBOmolecularmedicine.2012;4(3):143-59.21. SalmenaL,PolisenoL,TayY,KatsL,PandolfiPP.AceRNAhypothesis:theRosettaStoneofahiddenRNAlanguage?Cell.2011;146(3):353-8.22. DenzlerR,AgarwalV,StefanoJ,BartelDP,StoffelM.AssessingtheceRNAhypothesiswithquantitativemeasurementsofmiRNAandtargetabundance.Molecularcell.2014;54(5):766-76.23. CuiH,OnyangoP,BrandenburgS,WuY,HsiehC-L,FeinbergAP.LossofimprintingincolorectalcancerlinkedtohypomethylationofH19andIGF2.Cancerresearch.2002;62(22):6442-6.24. ZhuangM,GaoW,XuJ,WangP,ShuY.Thelongnon-codingRNAH19-derivedmiR-675modulateshumangastriccancercellproliferationbytargetingtumorsuppressorRUNX1.Biochemicalandbiophysicalresearchcommunications.2014;448(3):315-22.25. Tsang