Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
Oncogene. 2019 Nov;38(45):7060-7072. doi: 10.1038/s41388-019-0947-7. Epub 2019 Aug 13.
Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.
环状 RNA（circRNAs）的表达失调与多种人类疾病有关，包括许多类型的癌症。尽管环状 RNA 与癌症的联系越来越紧密，但在转移性去势抵抗性前列腺癌（导致前列腺癌死亡的主要原因）中，环状 RNA 的特征描述有限。在这里，通过对 47 个转移性去势抵抗性前列腺癌样本的外显子捕获 RNA-seq 数据集和患者来源异种移植（PDX）和细胞模型的核糖体缺失和 RNase R RNA-seq 的分析，我们从关键的前列腺癌驱动基因雄激素受体（AR）中鉴定出 13 个环状 RNA。我们验证并描述了前四个最丰富的、具有临床意义的 AR 环状 RNA。这些 AR 环状 RNA 的表达在 PDX 的去势抵抗进展过程中上调。这种上调不是由于这些肿瘤中环状 RNA 形成的全局增加。相反，在临床样本和 PDX 中，AR 环状 RNA 的水平与线性 AR 转录本（AR 和 AR 变体）的水平强烈相关，表明存在转录调节机制。在培养的细胞中，雄激素抑制这些 AR 环状 RNA 和线性 AR 转录本的表达，而抗雄激素可减弱这种抑制作用。通过核/细胞质分离和 RNA 原位杂交试验，我们证明了这些 AR 环状 RNA 主要位于细胞质中，表明其可能具有细胞质功能。总的来说，这是首次对来自 AR 基因的环状 RNA 进行全面特征描述。与线性 AR 转录本相比，这些 AR 环状 RNA 具有更强的对外切核酸酶的抗性和在患者血浆中的检测能力，因此这些 AR 环状 RNA 可能作为 AR/AR 变体表达和去势抵抗性前列腺癌进展的替代循环标志物。
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