Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer

被引：32

作者：

Cao, Subing ^{[1
]}

Ma, Tianfang ^{[1
]}

Ungerleider, Nathan ^{[2
]}

Roberts, Claire ^{[2
]}

Kobelski, Margaret ^{[1
]}

Jin, Lianjin ^{[1
]}

Concha, Monica ^{[2
]}

Wang, Xia ^{[2
]}

Baddoo, Melody ^{[2
]}

Nguyen, Holly M. ^{[3
]}

Corey, Eva ^{[3
]}

Fazli, Ladan ^{[4
]}

Ledet, Elisa ^{[5
]}

Zhang, Rubin ^{[5
]}

Silberstein, Jonathan L. ^{[5
]}

Zhang, Wensheng ^{[6
]}

Zhang, Kun ^{[6
]}

Sartor, Oliver ^{[5
]}

Dong, Xuesen ^{[4
]}

Flemington, Erik K. ^{[2
]}

Dong, Yan ^{[1
]}

机构：

[1] Tulane Univ, Sch Med, Dept Struct & Cellular Biol, Tulane Canc Ctr, 1430 Tulane Ave, New Orleans, LA 70112 USA

[2] Tulane Univ, Sch Med, Dept Pathol, Tulane Canc Ctr, New Orleans, LA 70112 USA

[3] Univ Washington, Dept Urol, Seattle, WA 98195 USA

[4] Univ British Columbia, Vancouver Prostate Ctr, Dept Urol Sci, Vancouver, BC, Canada

[5] Tulane Univ, Sch Med, Dept Med, Tulane Canc Ctr, New Orleans, LA 70112 USA

[6] Xavier Univ Louisiana, Dept Comp Sci, Bioinformat Facil, Xavier RCMI Ctr Canc Res, New Orleans, LA USA

来源：

ONCOGENE | 2019年 / 38卷 / 45期

基金：

美国国家卫生研究院;

关键词：

TRANSLATION; EXPRESSION; PROGRESSION; LANDSCAPE;

D O I：

10.1038/s41388-019-0947-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：7060 / 7072

页数：13

共 45 条

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