Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Germany.
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
Mol Oncol. 2018 Feb;12(2):256-266. doi: 10.1002/1878-0261.12164. Epub 2018 Jan 4.
Deregulation of the insulin-like growth factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development- and tissue-dependent manner and has been implicated in a broad range of malignancies including prostate cancer (PCa). Loss of imprinting (LOI) usually results in bi-allelic gene expression and increased levels of IGF2. However, the regulatory mechanisms and the pathophysiological impact of altered IGF2 expression in PCa remain elusive. Here, we show that in contrast to many other tumors, IGF2 mRNA and protein levels were decreased in 80% of PCa in comparison with non-neoplastic adjacent prostate and were independent of LOI status. Instead, IGF2 expression in both tumors and adjacent prostate depended on preferential usage of the IGF2 promoters P3 and P4. Decreased IGF2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with IGF2 expression in the 20% of PCa where IGF2 was higher in tumors than in adjacent prostate. We conclude that IGF2 is downregulated in most PCa and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. PCa differs from other tumors in that IGF2 expression is mainly regulated through methylation of promoter-specific and not by imprinting. Targeting of promoter-specific regions may have relevance for the adjuvant treatment of PCa.
胰岛素样生长因子 (IGF) 轴的失调和 IGF 系统成分的失衡已在不同肿瘤类型中被描述为潜在的治疗靶点。IGF2 是一种主要的胚胎生长因子和 IGF 信号的重要激活剂。它通过印迹在发育和组织依赖性方式进行调节，并与包括前列腺癌 (PCa) 在内的广泛恶性肿瘤有关。印迹丢失 (LOI) 通常导致 IGF2 的双等位基因表达和水平增加。然而，改变的 IGF2 表达在 PCa 中的调节机制和病理生理影响仍不清楚。在这里，我们表明与许多其他肿瘤相反，与非肿瘤相邻前列腺相比，80%的 PCa 中 IGF2 mRNA 和蛋白水平降低，且与 LOI 状态无关。相反，两种肿瘤和相邻前列腺中的 IGF2 表达取决于 IGF2 启动子 P3 和 P4 的优先使用。肿瘤中 IGF2 表达的降低与这两个启动子的高度甲基化密切相关。启动子 P4 中的 A 区域的甲基化与 IGF2 在肿瘤中高于相邻前列腺的 20%的 PCa 中的表达特别相关。我们得出结论，大多数 PCa 中 IGF2 表达下调，并且可能在肿瘤发展的早期阶段或在化疗和雄激素剥夺期间特别相关。PCa 与其他肿瘤不同之处在于，IGF2 表达主要通过启动子特异性的甲基化而不是印迹来调节。针对启动子特异性区域的靶向可能与 PCa 的辅助治疗有关。
