Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p
Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p
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DOI：
10.1002/1878-0261.12405
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发表时间：
2019-02-01
影响因子：
6.6
通讯作者：
Seki, Naohiko
中科院分区：
文献类型：
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作者：
Arai, Takayuki;Kojima, Satoko;Seki, Naohiko
雄激素剥夺疗法经常用于治疗前列腺癌（PCa），但可能会出现耐药性，这种情况称为去势抵抗性前列腺癌（CRPC）。因此，鉴定CRPC的新方法对于设计有效的PCa治疗是重要的。通过RNA测序分析microRNA（miRNA）表达特征表明，miR-455-双链体的过客链和引导链（分别为miR-455- 5 p和miR-455- 3 p）在PCa细胞中充当抗肿瘤miRNA。miRNA乘客链参与癌症发病机制是miRNA功能的一个新概念。基于癌症基因组图谱中的大型患者队列，8个miR-455- 5 p/-3p靶基因的表达（PIR：P = 0.0137，LRP 8：P = 0.0495，IGFBP3：P = 0.0172，DMBX1：P = 0.0175，CCDC 64：P = 0.0446，TUBB 1：P = 0.0149，KIF 21 B：P = 0.0336，NFAM 1：P = 0.0336）P = 0.0013）与PCa患者预后不良显著相关。在这里，我们专注于PIR（pirin），cupin超家族的一个高度保守的成员。PIR表达受miR-455- 5 p直接调节，并且PIR过表达在对前列腺癌敏感的手术标本和CRPC尸检标本中检测到。使用siRNA或抑制剂（双酰胺）的功能丧失试验表明，下调PIR表达阻断了癌细胞的迁移和侵袭。此外，miR-455- 5 p/PIR轴有助于癌细胞的侵袭性。提示PIR可能是诊断HSPC和CRPC的一个有前景的指标。此外，靶向PIR的CRPC治疗策略在未来可能成为可能。鉴定抗肿瘤miRNA，包括miRNA乘客链，可能有助于开发CRPC的新诊断标志物和治疗策略。
Androgen deprivation therapy is frequently used to treat prostate cancer (PCa), but resistance can occur, a condition known as castration-resistant prostate cancer (CRPC). Thus, novel approaches for identification of CRPC are important for designing effective PCa treatments. Analysis of microRNA (miRNA) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR-455-duplex (miR-455-5p and miR-455-3p, respectively) acted as antitumor miRNAs in PCa cells. The involvement of miRNA passenger strands in cancer pathogenesis is a novel concept for miRNA functionality. Based on a large patient cohort in The Cancer Genome Atlas, expression of eight miR-455-5p/-3p target genes (PIR: P = 0.0137, LRP8: P = 0.0495, IGFBP3: P = 0.0172, DMBX1: P = 0.0175, CCDC64: P = 0.0446, TUBB1: P = 0.0149, KIF21B: P = 0.0336, and NFAM1: P = 0.0013) was significantly associated with poor prognosis of PCa patients. Here, we focused on PIR (pirin), a highly conserved member of the cupin superfamily. PIR expression was directly regulated by miR-455-5p, and PIR overexpression was detected in hormone-sensitive prostate cancer (HSPC) surgical specimens and CRPC autopsy specimens. Loss-of-function assays using siRNA or an inhibitor (bisamide) showed that downregulation of PIR expression blocked cancer cell migration and invasion. Moreover, the miR-455-5p/PIR axis contributed to cancer cell aggressiveness. These results suggest that PIR might be a promising diagnostic marker for HSPC and CRPC. Furthermore, CRPC treatment strategies targeting PIR may be possible in the future. Identification of antitumor miRNAs, including miRNA passenger strands, may contribute to the development of new diagnostic markers and therapeutic strategies for CRPC.