胃肠道间质瘤(GIST)是最常见的胃肠道间质瘤。III型受体酪氨酸激酶的功能增益,KIT,或PDGFRA驱动大部分GIST。以前,我们小组报告说,沉默衔接分子SH3结合蛋白2(SH3BP2)下调KIT和PDGFRA以及小眼症相关转录因子(MITF)水平,并降低肿瘤生长.这项研究表明,SH3BP2沉默也降低了ETV1的水平,ETV1是GIST生长所需的因素。为了剖析GIST细胞中的SH3BP2通路,我们在SH3BP2沉默的GIST细胞系中进行了miRNA阵列。在最上调的miRNA中,我们发现miR-1246和miR-5100被预测为靶向MITF和ETV1.这些miRNA的过表达导致MITF和ETV1水平降低。在这种情况下,细胞活力和细胞周期进程受到影响,观察到BCL2和CDK2的减少。有趣的是,MITF的过表达增强了细胞增殖并显著挽救了miRNA转导细胞的活力。总之,KIT-SH3BP2-MITF/ETV1途径在GIST细胞存活和增殖中值得考虑。
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Gain of function in receptor tyrosine kinases type III, KIT, or PDGFRA drives the majority of GIST. Previously, our group reported that silencing of the adaptor molecule SH3 Binding Protein 2 (
SH3BP2) downregulated KIT and PDGFRA and microphthalmia-associated transcription factor (MITF) levels and reduced tumor growth. This study shows that
SH3BP2 silencing also decreases levels of ETV1, a required factor for GIST growth. To dissect the
SH3BP2 pathway in GIST cells, we performed a miRNA array in
SH3BP2-silenced GIST cell lines. Among the most up-regulated miRNAs, we found miR-1246 and miR-5100 to be predicted to target MITF and ETV1. Overexpression of these miRNAs led to a decrease in MITF and ETV1 levels. In this context, cell viability and cell cycle progression were affected, and a reduction in BCL2 and CDK2 was observed. Interestingly, overexpression of MITF enhanced cell proliferation and significantly rescued the viability of miRNA-transduced cells. Altogether, the KIT-
SH3BP2-MITF/ETV1 pathway deserves to be considered in GIST cell survival and proliferation.