RNA splicing and splicing regulator changes in prostate cancer pathology.
RNA splicing and splicing regulator changes in prostate cancer pathology.
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DOI：
10.1007/s00439-017-1792-9
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发表时间：
2017-09
期刊：
影响因子：
5.3
通讯作者：
Elliott DJ
中科院分区：
文献类型：
--
作者：
Munkley J;Livermore K;Rajan P;Elliott DJ
mRNA剪接模式的变化与前列腺癌进展中的关键病理机制相关。雄激素受体（缩写为AR）转录因子是前列腺癌病理学的主要驱动因素，并由雄激素类固醇激素激活。通过激活的AR选择替代启动子可以通过切换mRNA同种型产生来关键地改变基因功能，包括产生正常肿瘤抑制基因TSC 2的促癌同种型。许多雄激素调节基因产生选择性剪接的mRNA亚型，包括前列腺特异性剪接亚型ST 6 GALNAC 1 mRNA。ST 6 GALNAC 1编码唾液酸转移酶，其催化对细胞移动性重要的癌症相关sTn抗原的合成。在前列腺癌发展早期发生的遗传重排将ERG癌基因表达置于雄激素调节的TMPRSS 2启动子的控制下，以劫持细胞行为。该TMPRSS 2-ERG融合基因在侵袭性与局限性前列腺癌中显示不同的选择性剪接模式。替代AR mRNA同种型通过提供前列腺癌细胞可以在有限的血清雄激素浓度下生长的机制，在前列腺癌耐药性的产生中发挥关键作用。许多剪接调节蛋白改变前列腺癌的表达模式，可能有助于推动疾病进展的关键阶段。SRRM 4的上调在神经内分泌前列腺癌中建立了神经元剪接模式剪接调节剂Sam 68和Tra 2 β增加前列腺癌中的表达。调节SR蛋白活性的SR蛋白激酶SRPK 1在前列腺癌中上调，并且已经在小鼠模型中作为潜在的治疗靶点给出了令人鼓舞的结果。
Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2–ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.
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影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
16.6
作者：
Best, Andrew;James, Katherine;Dalgliesh, Caroline;Hong, Elaine;Kheirolahi-Kouhestani, Mahsa;Curk, Tomaz;Xu, Yaobo;Danilenko, Marina;Hussain, Rafiq;Keavney, Bernard;Wipat, Anil;Klinck, Roscoe;Cowell, Ian G.;Lee, Ka Cheong;Austin, Caroline A.;Venables, Julian P.;Chabot, Benoit;Koref, Mauro Santibanez;Tyson-Capper, Alison;Elliott, David J.
通讯作者：
Elliott, David J.
影响因子：
16.6
作者：
Feracci M;Foot JN;Grellscheid SN;Danilenko M;Stehle R;Gonchar O;Kang HS;Dalgliesh C;Meyer NH;Liu Y;Lahat A;Sattler M;Eperon IC;Elliott DJ;Dominguez C
通讯作者：
Dominguez C
影响因子：
--
作者：
Gillis JL;Selth LA;Centenera MM;Townley SL;Sun S;Plymate SR;Tilley WD;Butler LM
通讯作者：
Butler LM