Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California, San Francisco, CA, USA.
Carcinogenesis. 2019 Jul 4;40(5):633-642. doi: 10.1093/carcin/bgz058.
The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21-22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes-miR-3622, miR-3622b, miR-383-that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p-miR-4288-by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.
前列腺癌（PCa）的基因组特征是 8p21-22 染色体区域缺失，该缺失与肿瘤分级显著相关，并与预后不良相关。我们提出并验证了一个新颖的、具有变革意义的假说，即该区域与一组 microRNA 基因-miR-3622、miR-3622b、miR-383 相关，这些基因在 PCa 中丢失，并在 PCa 进展和转移中发挥重要的机制作用。在本研究中，我们扩展了这一假说，评估了位于 8p 染色体上的 microRNA 基因 miR-4288 的作用，使用了临床样本和细胞系。我们的数据表明：（i）miR-4288 在原发性前列腺肿瘤和细胞系中广泛下调；（ii）miR-4288 在转移性去势抵抗性 PCa 中丢失；（iii）miR-4288 下调是与种族相关的 PCa 改变，在白种人中常见，而在非裔美国人中不常见；（iv）在白种人中，miR-4288 与肿瘤分级增加和高血清前列腺特异性抗原相关，表明 miR-4288 下调/丢失可能与白种人中的肿瘤进展相关；（v）miR-4288 具有作为预测侵袭性/转移的分子生物标志物的显著潜力；（vi）miR-4288 具有抑制增殖、抗侵袭和上皮-间质转化的作用；（vi）miR-4288 直接抑制转移/侵袭相关基因 MMP16 和 ROCK1 的表达。因此，本研究证明了位于 PCa 中经常缺失区域的新型 miRNA 的肿瘤抑制作用，加强了我们的假说，即该基因座通过 microRNA 基因的丢失与 PCa 疾病进展有因果关系。我们的研究表明，miR-4288 可能是一种新的生物标志物和治疗靶点，特别是在白种人中。
