Department of Pathology and Immunology, Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9172-7. doi: 10.1073/pnas.1100489108. Epub 2011 May 12.
Transcription-induced chimeric RNAs, possessing sequences from different genes, are expected to increase the proteomic diversity through chimeric proteins or altered regulation. Despite their importance, few studies have focused on chimeric RNAs especially regarding their presence/roles in human cancers. By deep sequencing the transcriptome of 20 human prostate cancer and 10 matched benign prostate tissues, we obtained 1.3 billion sequence reads, which led to the identification of 2,369 chimeric RNA candidates. Chimeric RNAs occurred in significantly higher frequency in cancer than in matched benign samples. Experimental investigation of a selected 46 set led to the confirmation of 32 chimeric RNAs, of which 27 were highly recurrent and previously undescribed in prostate cancer. Importantly, a subset of these chimeras was present in prostate cancer cell lines, but not detectable in primary human prostate epithelium cells, implying their associations with cancer. These chimeras contain discernable 5' and 3' splice sites at the RNA junction, indicating that their formation is mediated by splicing. Their presence is also largely independent of the expression of parental genes, suggesting that other factors are involved in their production and regulation. One chimera, TMEM79-SMG5, is highly differentially expressed in human cancer samples and therefore a potential biomarker. The prevalence of chimeric RNAs may allow the limited number of human genes to encode a substantially larger number of RNAs and proteins, forming an additional layer of cellular complexity. Together, our results suggest that chimeric RNAs are widespread, and increased chimeric RNA events could represent a unique class of molecular alteration in cancer.
转录诱导的嵌合 RNA 具有来自不同基因的序列，有望通过嵌合蛋白或改变调节来增加蛋白质组的多样性。尽管它们很重要，但很少有研究关注嵌合 RNA，特别是它们在人类癌症中的存在/作用。通过对 20 个人类前列腺癌和 10 个匹配的良性前列腺组织的转录组进行深度测序，我们获得了 13 亿个序列读段，从而鉴定出了 2369 个嵌合 RNA 候选物。嵌合 RNA 在癌症中的发生频率明显高于匹配的良性样本。对选定的 46 个嵌合 RNA 的实验研究证实了 32 个嵌合 RNA 的存在，其中 27 个在前列腺癌中高度重复且以前未被描述。重要的是，这些嵌合 RNA 中的一部分存在于前列腺癌细胞系中，但在原代人前列腺上皮细胞中不可检测，这表明它们与癌症有关。这些嵌合 RNA 在 RNA 连接处具有可识别的 5'和 3'剪接位点，表明它们的形成是由剪接介导的。它们的存在也在很大程度上独立于亲本基因的表达，这表明其他因素参与了它们的产生和调节。一个嵌合 RNA，TMEM79-SMG5，在人类癌症样本中表达差异很大，因此可能是一个潜在的生物标志物。嵌合 RNA 的普遍性可能允许有限数量的人类基因编码大量的 RNA 和蛋白质，从而形成细胞复杂性的另一个层次。总之，我们的研究结果表明，嵌合 RNA 广泛存在，并且增加的嵌合 RNA 事件可能代表癌症中独特的一类分子改变。
