Eur Urol:Y染色体上LncRNA对前列腺癌的促进作用机制获进展

2018-12-16 BioWorld iNature

前列腺癌(PCa)是世界上最常见的恶性肿瘤之一,是男性发病率第二的癌症(仅次于肺癌)。Y染色体是唯一的男性性别决定染色体,因此在男性特异性器官发育中起重要作用(如前列腺),Y染色体很可能涉及男性特异性疾病(如前列腺癌)。

前列腺癌(PCa)是世界上最常见的恶性肿瘤之一,是男性发病率第二的癌症(仅次于肺癌)。Y染色体是唯一的男性性别决定染色体,因此在男性特异性器官发育中起重要作用(如前列腺),Y染色体很可能涉及男性特异性疾病(如前列腺癌)。

Y染色体定位因子可能是潜在的基因治疗靶点,因为Y染色体是单倍体,而且基因组很小,比其他染色体的基因编辑效率更高。女性没有Y染色体也能健康生活,提示Y染色体上的因子作物药物靶点,全身副作用可能更小,对于治疗具有很大的优势。

2018年12月7日,第二军医大学孙颖浩院士、蒋俊锋作为共同通讯作者在泌尿学领域顶尖期刊European Urology杂志发表题为“The Long Noncoding RNA TTTY15, Which Is Located on the Y Chromosome, Promotes Prostate Cancer Progression by Sponging let-7”的LncRNA研究论文。该研究发现并证实位于Y染色体上的LncRNA-TTTY15在大多数前列腺癌患者中高度表达,通过两种不同的CRISPR/Cas9策略敲除TTTY15,证实TTTY15通过对miRNA-let-7的海绵作用作为前列腺癌的促癌因子。这一发现对于前列腺癌的治疗具有非常积极的意义。

LncRNA在很多生理和病理过程中发挥重要作用,当然也包括前列腺癌。有一些关于LncRNA参与前列腺癌的发生发展的研究报道,但是定位于Y染色体的LncRNA在前列腺癌中的作用尚未有系统研究。

2017年孙颖浩院士团队就在European Urology杂志发表了基于65位中国患者的前列腺癌组织和正常组织的全转录数据库,此次,研究团队通过分析该数据库,发现位于Y染色体的LncRNA-TTTY15在前列腺癌组织中过表达倍数最多。

通过TCGA数据库分析来自其他种族的前列腺癌患者转录组数据,发现TTTY15同样在前列腺癌组织中高表达。

此次,研究团队通过更大规模的临床样本转录组测序,进一步确认TTTY15在前列腺癌组织中高表达。

通过过表达和敲低实验,证实TTTY15促进前列腺癌细胞的增殖和迁移。

通过两种不同的CRISPR/Cas9策略敲除该LncRNA,在体外和体内均抑制前列腺癌细胞生长。

第一种策略:使用双sgRNA引导的CRISPR/Cas9系统,实现TTTY15的整个片段敲除。

第二种策略:使用CRISPR/Cas9介导的基因敲入,敲入转录终止子,终止TTTY15的转录。

敲除策略一:双sgRNA实现LncRNA的大片段敲除

敲除策略二:敲入转录终止子序列,终止LncRNA转录

在这两种敲除TTTY15的细胞中过表达TTTY15,恢复了癌细胞减弱的增殖能力。这一Rescue实验进一步证实TTTY15对前列腺癌的促进作用。

TTTY15促进前列腺癌的机制研究

FOXA1是TTTY15转录的上游调节因子,TTTY15通过海绵作用吸附miRNA-let-7,let-7表达水平的减少,促进了CDK6和FN1的表达,从而促进了前列腺癌的发展。

总的来说,位于Y染色体的LncRNA-TTTY15在大多数前列腺癌组织中表达上调,并通过对let-7的海绵作用来促进前列腺癌进展。

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    2018-12-18 xzw113
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    2018-12-18 周虎
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    2018-12-16 1247a70em33暂无昵称

    学习了

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最近的进展表明雄激素/雄激素受体(AR)靶向治疗对患有转移性前列腺癌的治疗作用有限,这种情况部分是由于前列腺癌可以适应性的变换到不依赖于雄激素/AR途径来进行生存和生长,从而产生治疗抗性。肿瘤缺氧被认为是治疗抗性产生的一个主要起因。然而,精确的机制仍旧不清楚。最近,有研究人员报道了在缺氧条件下的长期的雄激素阻断治疗(ADT)能够诱导适应性的不依赖雄激素/AR,从而产生对雄激素/AR靶向治疗的抗性,

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大多数前列腺癌患者会在雄激素阻断治疗后恶化发展到去势抵抗性(CRPC)状态,尽管新的有效的抗雄激素药物的开发,比如恩杂鲁胺(ENZ)能够延长CRPC患者的生存,但是ENZ抗性会很快产生。雄激素受体(AR)的重新激活是抗性产生的一个主要机制。最近,有研究人员通过其体内来源的ENZ抗性模型,发现STAT3转录因子不仅在核定位中增加,同时能够结合和促进AR活性。研究人员观察到了在ENZ抗性细胞中STAT

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前列腺癌(PC)是男性第二大致死性癌症,因此,早期对恶性和良性肿瘤的区分的生物标记是需要的。之前的研究表明,G蛋白信号2(RGS2)调控因子在PC中下调,然而,潜在的机制还没有研究清楚。另外,RGS2表达的异常在其他阳性和阴性诊断的恶性肿瘤中存在。最近,有研究人员在PC恶化过程中评估了RGS2的表达,并考虑了对肿瘤表型的调控和影响,还评估了它的预后值。研究发现,RGS2在早期PC中的下调是由缺氧引