Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China.
Prostate. 2012 Aug 1;72(11):1171-8. doi: 10.1002/pros.22466. Epub 2011 Dec 7.
Castration-resistant prostate cancer (CRPC) is a leading cause of cancer-related deaths in elder men. This disease has limited therapeutic options and poor prognosis as the underlying molecular mechanisms are not clearly understood. Given the emerging roles of microRNA (miRNA) as a key regulator, we postulated that miRNA may play a significant role in CRPC formation.
miR-146a levels in 15 androgen-dependent prostate cancer (ADPC) tissues and 5 CRPC tissues were measured by qRT-PCR. Effects of miR-146a in cell proliferation and migration in vitro and in vivo were evaluated by MTT assay, colony formation assay, transwell migratory assay, and tumor formation assay, respectively.
we found that miR-146a expression was significantly decreased in CRPC tissues compared to ADPC tissues. Functional analyses showed that ectopic overexpression of miR-146a in androgen-independent cell lines not only inhibited cell growth, colony formation, and migration in vitro, but also reduced tumorigenicity and angiogenesis in vivo. Mechanistic studies revealed that miR-146a repressed the expression of EGFR through binding to its 3'-untranslated region. Also, miR-146a inhibited the expression of MMP2, one of the most important genes in tumor progression. Moreover, downregulation of p-ERK expression significantly abrogated miR-146a-induced prostate cancer cell proliferation.
Our findings suggest that ubiquitous loss of miR-146a is a critical mechanism for overexpression of EGFR in CRPC, which is crucial to better understanding the pathogenesis of CRPC.
去势抵抗性前列腺癌（CRPC）是导致老年男性癌症相关死亡的主要原因。由于潜在的分子机制尚不清楚，这种疾病的治疗选择有限，预后较差。鉴于 microRNA（miRNA）作为关键调节因子的作用不断显现，我们推测 miRNA 可能在 CRPC 形成中发挥重要作用。
通过 qRT-PCR 测量 15 例雄激素依赖性前列腺癌（ADPC）组织和 5 例 CRPC 组织中的 miR-146a 水平。通过 MTT 测定、集落形成测定、Transwell 迁移测定和肿瘤形成测定分别评估 miR-146a 在体外和体内对细胞增殖和迁移的影响。
我们发现与 ADPC 组织相比，CRPC 组织中 miR-146a 的表达明显降低。功能分析表明，在雄激素非依赖性细胞系中过表达 miR-146a 不仅抑制了体外细胞生长、集落形成和迁移，而且还降低了体内的肿瘤发生和血管生成。机制研究表明，miR-146a 通过结合其 3'非翻译区来抑制 EGFR 的表达。此外，miR-146a 抑制了 MMP2 的表达，MMP2 是肿瘤进展中最重要的基因之一。此外，下调 p-ERK 表达可显著阻断 miR-146a 诱导的前列腺癌细胞增殖。
我们的研究结果表明，miR-146a 的普遍缺失是 CRPC 中 EGFR 过表达的关键机制，这对于更好地理解 CRPC 的发病机制至关重要。
