Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
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DOI：
10.1158/0008-5472.can-16-3089
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发表时间：
2017-10-01
期刊：
影响因子：
11.2
通讯作者：
Jarrard, David F.
中科院分区：
文献类型：
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作者：
Damaschke, Nathan A.;Yang, Bing;Jarrard, David F.
印迹缺失（LOI）是一种表观遗传事件，它放松了对基因表达的等位基因特异性限制。经历LOI的一个基因是旁分泌胰岛素样生长因子IGF 2，其在衰老和肿瘤发生期间通常出现在人类前列腺组织中。然而，IGF 2 LOI和前列腺肿瘤发生之间的关系尚未建立功能。在这项研究中，我们建立了一个小鼠模型，在Igf 2-H19印记控制区的CTCF结合位点突变，消除CTCF绝缘子活性，导致双等位基因Igf 2表达，模拟衰老诱导的LOI水平增加。我们发现Igf 2 LOI增加了前列腺上皮内瘤变（PIN）的患病率和严重程度，PIN是一种癌前病变。将Nkx3.1缺陷工程化到我们的模型中以相加的方式增加了PIN病变的频率。携带LOI的前列腺显示MAPK信号传导和上皮增殖增加。在人前列腺组织阵列中，我们记录了良性组织中IGF 2水平与磷酸化ERK和磷酸化AKT水平的正相关性。总体而言，我们的研究结果表明Igf 2 LOI本身足以通过上调关键的癌症相关信号通路来增加前列腺肿瘤发展的速率。(C)2017年AACR。
Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. (C) 2017 AACR.