Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis
Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis
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DOI：
10.18632/oncotarget.7833
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发表时间：
2016-04-12
期刊：
影响因子：
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通讯作者：
Cimmino, Amelia
中科院分区：
文献类型：
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作者：
Olivieri, Michele;Ferro, Matteo;Cimmino, Amelia
研究表明，超保守区（ucr）可以产生具有不同表达谱的非编码RNA转录物（t - ucr），并在多种癌症的病理生理中发挥功能作用。这些功能与膀胱癌（BlCa）发病机制的相关性是推测性的。为了阐明这种相关性，我们首先使用全基因组分析来评估t - ucr在BlCa组织中的表达。使用定制T-UCR微阵列分析正常膀胱组织和BlCa标本的两个数据集，鉴定出超保守RNA （uc）。8+是BlCa组织中表达上调最多的T-UCR，尽管其表达低于癌周膀胱组织。这些结果通过实时PCR和原位杂交在BlCa组织上得到证实。尽管加州大学。8+位于锌指转录因子CASZ1的内含子1内，被转录的非编码RNA编码uc。8+独立于CASZ1表达。体外实验评价uc的作用。8+沉默，显示癌细胞侵袭、迁移和增殖能力显著下降。在此基础上，我们提出并验证了uc的交互模型。8+从BlCa细胞的细胞核穿梭到细胞质中，与microRNA (miR)-596相互作用，共同促进BlCa的发生和发展。通过计算分析，我们研究了mir -结合域的可达性，这是由uc内的碱基配对相互作用决定的。8+预测了膀胱组织的二级结构、RNA结合亲和力和RNA种类丰度。8+是miR-596的天然诱饵。加州大学。8+上调导致MMP9表达增加，增加BlCa细胞的侵袭潜能。进化上保守的DNA区域之间的这些相互作用表明，自然选择保留了这个使用RNA调节miR水平的潜在调控层，为开发早期诊断和预后的有用标记以及开发新的基于RNA的癌症治疗开辟了可能性。
Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.