Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305, CA, USA.
Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, 94305, CA, USA.
Gynecol Oncol. 2018 May;149(2):388-393. doi: 10.1016/j.ygyno.2018.03.007. Epub 2018 Mar 12.
Low-grade endometrial stromal sarcomas (LGESS) harbor chromosomal translocations that affect proteins associated with chromatin remodeling Polycomb Repressive Complex 2 (PRC2), including SUZ12, PHF1 and EPC1. Roughly half of LGESS also demonstrate nuclear accumulation of β-catenin, which is a hallmark of Wnt signaling activation. However, the targets affected by the fusion proteins and the role of Wnt signaling in the pathogenesis of these tumors remain largely unknown.
Here we report the results of a meta-analysis of three independent gene expression profiling studies on LGESS and immunohistochemical evaluation of nuclear expression of β-catenin and Lef1 in 112 uterine sarcoma specimens obtained from 20 LGESS and 89 LMS patients.
Our results demonstrate that 143 out of 310 genes overexpressed in LGESS are known to be directly regulated by SUZ12. In addition, our gene expression meta-analysis shows activation of multiple genes implicated in Wnt signaling. We further emphasize the role of the Wnt signaling pathway by demonstrating concordant nuclear expression of β-catenin and Lef1 in 7/16 LGESS.
Based on our findings, we suggest that LGESS-specific fusion proteins disrupt the repressive function of the PRC2 complex similar to the mechanism seen in synovial sarcoma, where the SS18-SSX fusion proteins disrupt the mSWI/SNF (BAF) chromatin remodeling complex. We propose that these fusion proteins in LGESS contribute to overexpression of Wnt ligands with subsequent activation of Wnt signaling pathway and formation of an active β-catenin/Lef1 transcriptional complex. These observations could lead to novel therapeutic approaches that focus on the Wnt pathway in LGESS.
低度子宫内膜间质肉瘤（LGESS）存在影响染色质重塑多梳抑制复合物 2（PRC2）相关蛋白的染色体易位，包括 SUZ12、PHF1 和 EPC1。大约一半的 LGESS 还表现出β-连环蛋白的核积累，这是 Wnt 信号激活的标志。然而，融合蛋白影响的靶标以及 Wnt 信号在这些肿瘤发病机制中的作用在很大程度上仍然未知。
我们在此报告了对 3 项独立的 LGESS 基因表达谱研究的荟萃分析结果，以及对 20 例 LGESS 和 89 例 LMS 患者的 112 例子宫肉瘤标本进行β-连环蛋白核表达和 Lef1 的免疫组织化学评估的结果。
我们的结果表明，在 LGESS 中过表达的 310 个基因中的 143 个已知是由 SUZ12 直接调控的。此外，我们的基因表达荟萃分析显示，多个与 Wnt 信号相关的基因被激活。我们通过证明在 7/16 例 LGESS 中β-连环蛋白和 Lef1 的核表达一致，进一步强调了 Wnt 信号通路的作用。
基于我们的发现，我们提出 LGESS 特异性融合蛋白破坏 PRC2 复合物的抑制功能，类似于滑膜肉瘤中所见的机制，其中 SS18-SSX 融合蛋白破坏 mSWI/SNF（BAF）染色质重塑复合物。我们提出，LGESS 中的这些融合蛋白导致 Wnt 配体的过表达，随后激活 Wnt 信号通路并形成活性β-连环蛋白/Lef1 转录复合物。这些观察结果可能导致针对 LGESS 中 Wnt 途径的新的治疗方法。
