PDF(Pubmed)
Abstract：
Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as \'Genesis\' and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.
摘要：
胃肠道间质瘤（GIST）是间质瘤，据信起源于Cajal（ICC）的间质细胞，通常由酪氨酸激酶受体（TKR）KIT或PDGFRA的过表达引起。这里,我们提供的证据表明，胚胎干细胞因子FOXD3，首先被确定为“创世纪”和功能在胃肠道和神经c细胞发育，与GIST发病机理有关；在体外，斑马鱼和FOXD3缺乏症的小鼠模型中都研究了其参与。共58例野生型GIST患者的样本用于分子分析，包括桑格序列，CGH和甲基化。使用免疫组织化学和Western印迹评估来获得FOXD3表达。此外,我们在组织样本和转染细胞中进行了体外功能研究，以确认鉴定的遗传变异的致病性。种系部分失活FOXD3序列变体（p。在分离的GIST患者中发现了R54H和p.Ala88_Gly91del）。染色体1p缺失是肿瘤中最常见的染色体异常。体外实验证明了在这些变体存在下FOXD3的损害。动物研究显示GI神经网络的破坏以及ICC中数量和分布的变化。FOXD3抑制人细胞中的KIT表达；其失活导致斑马鱼中ICC的增加，和老鼠一样，为FOXD3缺陷和KIT过表达之间的功能联系提供证据导致GIST形成。
