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首页> 美国卫生研究院文献>Neoplasia (New York N.Y.) >IDH1R132H Promotes Malignant Transformation of Benign Prostatic Epithelium by Dysregulating MicroRNAs: Involvement of IGF1R-AKT/STAT3 Signaling Pathway
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IDH1R132H Promotes Malignant Transformation of Benign Prostatic Epithelium by Dysregulating MicroRNAs: Involvement of IGF1R-AKT/STAT3 Signaling Pathway

机译：IDH1R132H通过失调的microRNA促进良性前列腺上皮的恶性转化：IGF1R-AKT / STAT3信号通路的参与

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Risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer (PCa). Mutations in isocitrate dehydrogenase (IDH) acquire an abnormal enzymatic activity, resulting in the production of 2-hydroxyglutarate and alterations in cellular metabolism, histone modification, and DNA methylation. Mutant IDH1 has been identified in various human malignancies, and IDH1R132H constituted the vast majority of mutational events of IDH1. Most recent studies suggested that IDH1 mutations define a methylator subtype in PCa. However, the function of IDH1R132H in PCa development and progression is largely unknown. In this study, we showed that the prevalence of IDH1R132H in Chinese PCa patients is 0.6% (2/336). Of note, IDH1R132H-mutant PCa patients lacked other canonical genomic lesions (e.g., ERG rearrangement, PTEN deletion) that are common in most other PCa patients. The in vitro experiment suggested that IDH1R132H can promote proliferation of benign prostate epithelial cell RWPE-1 when under the situation of low cytokine. It could also promote migration capacity of RWPE-1 cells. Mechanistically, IDH1R132H was an important regulator of insulin-like growth factor 1receptor (IGF1R) by downregulating a set of microRNAs (miR-141-3p, miR-7-5p, miR-223-3p). These microRNAs were repressed by the alteration of epigenetic modification to decrease the enrichment of active marker H3K4me3 or to increase repressive marker H3K27me3 at their promoters. Collectively, we proposed a novel model for an IDH1R132H-microRNAs-IGF1R regulatory axis, which might provide insight into the function of IDH1R132H in PCa development.
机译：使用分子特征进行风险分层可能有助于区分惰性与侵袭性前列腺癌（PCa）。异柠檬酸脱氢酶（IDH）中的突变获得异常的酶活性，导致2-羟基戊二酸的产生以及细胞代谢，组蛋白修饰和DNA甲基化的改变。已经在各种人类恶性肿瘤中鉴定出突变体IDH1，并且IDH1R132H构成了IDH1的绝大多数突变事件。最新研究表明，IDH1突变定义了PCa中的甲基化亚型。但是，IDH1R132H在PCa发育和进展中的功能很大程度上未知。在这项研究中，我们显示IDH1R132H在中国PCa患者中的患病率为0.6％（2/336）。值得注意的是，IDH1R132H突变的PCa患者缺乏其他大多数PCa患者常见的其他规范基因组损伤（例如ERG重排，PTEN缺失）。体外实验表明，在细胞因子低的情况下，IDH1R132H可以促进良性前列腺上皮细胞RWPE-1的增殖。它还可以提高RWPE-1细胞的迁移能力。从机制上讲，IDH1R132H通过下调一系列microRNA（miR-141-3p，miR-7-5p，miR-223-3p）是胰岛素样生长因子1受体（IGF1R）的重要调节剂。这些microRNA被表观遗传修饰的改变所抑制，以减少其启动子上活性标记H3K4me3的富集或增加抑制性标记H3K27me3。我们共同提出了一个IDH1R132H-microRNAs-IGF1R调控轴的新模型，该模型可能会提供IDH1R132H在PCa开发中的功能的见解。

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