A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition
A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition
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DOI：
10.1038/cdd.2017.69
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发表时间：
2017-07-01
影响因子：
12.4
通讯作者：
Saini, Sharanjot
中科院分区：
文献类型：
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作者：
Bucay, Nathan;Bhagirath, Divya;Saini, Sharanjot
前列腺癌基因组中最常见的改变是染色体 (chr) 8p21 的丢失，这与 NKX3.1 同源盒基因的丢失有关。 Chr8p21 缺失随着肿瘤分级的增加而显着增加，并且与前列腺癌 (PCa) 的不良预后相关，表明该区域在肿瘤进展中发挥着重要作用。最近的研究表明，除了 NKX3.1 之外，该区域还含有尚未确定的替代肿瘤抑制因子。我们提出了一种新颖的、范式转变的假设，即该位点与 miRNA 基因簇 miR-3622a/b 相关，该基因簇在 PCa 中发挥着至关重要的抑制作用。在这里，我们证明了 miR-3622a 在前列腺癌上皮间质转化 (EMT) 中的关键作用。显微解剖的人类 PCa 临床组织中的 MicroRNA 表达谱表明，miR-3622a 表达广泛下调，并且与不良生存结果和肿瘤进展显着相关。为了了解 miR-3622a 的功能意义，分别使用未转化的前列腺上皮细胞系和 PCa 细胞系进行敲低和过表达，然后进行功能测定。我们的数据表明，内源性 miR-3622a 表达对于维持正常和未转化前列腺细胞的上皮状态至关重要。 miR-3622a 表达在体外和体内抑制 PCa 的 EMT、进展和转移。此外，我们发现 miR-3622a 直接靶向 EMT 效应子 ZEB1 和 SNAI2。鉴于这些数据，我们提出 chr8p21 区域 miR-3622a 的频繁丢失会导致 EMT 状态的诱导，进而促进 PCa 的进展和转移。这项研究在前列腺癌领域具有潜在的重大意义，因为它鉴定了一个经常丢失的染色体区域的重要 miRNA 成分，在前列腺癌发生中发挥着关键作用，这是了解该位点的机制参与的非常重要的一步。此外，我们的研究表明 miR-3622a 是一种新型 PCa 生物标志物和开发针对晚期 PCa 治疗方案的潜在药物靶点。
The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b- that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-to-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.