Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer.
Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer.
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DOI：
10.18632/oncotarget.1769
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发表时间：
2014-02-15
期刊：
影响因子：
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通讯作者：
Helgason CD
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文献类型：
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作者：
Crea F;Watahiki A;Quagliata L;Xue H;Pikor L;Parolia A;Wang Y;Lin D;Lam WL;Farrar WL;Isogai T;Morant R;Castori-Eppenberger S;Chi KN;Wang Y;Helgason CD
转移性前列腺癌（PCa）仍然是一种无法治愈的疾病。长链非编码RNA（lncRNA）可能是癌症生物标志物和治疗靶点的一个被忽视的来源。因此，我们对来自临床标本的成对转移性/非转移性PCa异种移植物进行了RNA测序。最高度上调的转录物是L0C728606，其是现在命名为PCAT18的lncRNA。与11种其他正常组织相比，PCAT18在前列腺中特异性表达（p <0.05），与15种其他肿瘤相比，PCAT18在PCa中上调（p <0.001）。PCAT 18的癌症特异性上调在PCa和良性前列腺增生样品的独立数据集上得到证实（p <0.001）。PCAT18在血浆样品中可检测到，并且从健康个体到患有局限性和转移性PCa的那些个体逐渐增加（p <0.01）。我们鉴定了一个PCAT18相关的表达标签（PES），它是高度PCa特异性的，在转移性与原发性PCa样本中被激活（p <1E − 4，比值比> 2）。PES与雄激素受体（AR）信号传导显著相关。因此，AR激活在体外和体内显著上调PCAT18表达。PCAT 18沉默显著（p <0.001）抑制PCa细胞增殖并触发半胱天冬酶3/7活化，对非肿瘤细胞没有影响。PCAT18沉默还抑制PCa细胞迁移（p <0.01）和侵袭（p <0.01）。这些结果将PCAT 18定位为转移性PCa的潜在治疗靶标和生物标志物。
Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The most highly up-regulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E−4, odds ratio>2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on non-neoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.