MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer.
MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer.
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DOI：
10.1038/onc.2016.419
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发表时间：
2017-05-11
期刊：
影响因子：
8
通讯作者：
Saini S
中科院分区：
文献类型：
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作者：
Bucay N;Sekhon K;Yang T;Majid S;Shahryari V;Hsieh C;Mitsui Y;Deng G;Tabatabai ZL;Yamamura S;Calin GA;Dahiya R;Tanaka Y;Saini S
前列腺癌（PCa）的一个主要基因组改变是染色体（chr）8 p的频繁丢失，并在chr 8 p22位点存在一个共同的杂合性丢失（洛）区域。基因组研究表明，该基因座与临床显著PCa的发生和转移性疾病的进展有关。然而，该区域内的基因迄今尚未完全表征。在这里，我们首次证明了该区域的microRNA组分-miR-383-在前列腺癌中经常下调，在确定肿瘤起始潜力中起关键作用，并通过直接调节CD 44参与前列腺癌转移，CD 44是PCa肿瘤起始细胞（TIC）/干细胞的普遍存在的标志物。对PCa临床组织中miR-383的表达分析表明，miR-383的低表达与预后不良相关。功能数据表明，miR-383通过CD 44调节来调节PCa肿瘤起始/干细胞样细胞。miR-383的异位表达抑制了CD 44 + PCa细胞的肿瘤起始能力。此外，在PCa实验转移模型中观察到异位miR-383表达的“抗转移”作用。鉴于我们的研究结果，我们提出miR-383在chr 8 p22区域的频繁丢失导致肿瘤发生和前列腺癌转移。因此，我们已经确定了一个新的发现，长期观察到的基因组改变PCa干性和转移。我们的数据表明，miR-383表达的恢复可能是一种有效的治疗方式对PCa。重要的是，我们将miR-383确定为一种新的PCa组织诊断生物标志物，其潜力超过血清PSA。
A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region –miR-383- is frequently downregulated in prostate cancer, plays a critical role in determining tumor initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor initiating cells (TICs)/ stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggests that miR-383 regulates PCa tumor initiating/ stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor initiating capacity of CD44+ PCa cells. Also, ‘anti-metastatic’ effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggests that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.