生物
PDGFRA公司
原癌基因蛋白质c-kit
间质细胞
癌症研究
受体酪氨酸激酶
卡哈尔间质细胞
间充质干细胞
斑马鱼
干细胞
主旨
病理
分子生物学
干细胞因子
免疫组织化学
免疫学
受体
遗传学
基因
造血
医学
作者
Fabio R. Faucz,Anélia Horvath,Guillaume Assié,Madson Q. Almeida,Eva Szarek,Sosipatros A. Boikos,Anna Angelousi,Isaac Lévy,Andréa Gutierrez Maria,Ajay B. Chitnis,Cristina R. Antonescu,Rainer Claus,Jérôme Bertherat,Christoph Plass,Charis Eng,Constantine A. Stratakis
出处
期刊:Endocrine-related Cancer
[Bioscientifica]
日期:2023-08-14
卷期号:30 (10)
摘要
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.
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