KIT相关microRNA影响胃肠道间质瘤进展及预后的机制研究

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Up to now, dependable biomarker of prognosis of GISTs is still unavailable. Furthermore, secondary resistance to imatinib has become a serious problem of treatment. As the oncogene and therapeutic target of GISTs, KIT receptor has been well studied. Over the past years, miRNAs, which suggested to be one of the most important features contributing to carcinogenesis, have been discovered and their impact on carcinogenesis has been described, but we cannot find any systemic report of miRNAs which regulate KIT. We initially used bioinfomative technology and molecular biotechnology for selecting 3 miRNAs which specific target KIT and differentiated in GIST by risk level. This study which based on our primary research, aimed to discover microRNAs that target KIT and reveal the relationship between the discovered microRNAs and KIT expression in GISTs. We are going to reveal the role of miRNAs on evaluation of prognosis, discover the regulation of miRNAs on KIT expression. Furthermore, we are going to study the KIT inactivation through miRNAs, which might be another promising therapeutic method for GIST treatment.

胃肠道间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤，并已成为仅次于胃癌、肠癌的消化道肿瘤。目前尚无能准确评估GIST预后的可靠指标，且曾很有效的经典药物伊马替尼的耐药已成为目前GIST治疗的棘手问题，作为GIST肿瘤进展及靶向治疗的重要位点，KIT受体是研究的焦点。近年，miRNA在肿瘤进展及耐药方面的作用日益受到关注，但迄今尚无关于KIT相关miRNA在GIST病程中作用的系统报道。我们采用生物信息学及分子生物学技术筛选出3个以KIT为靶基因，并随肿瘤复发危险度呈差异表达的miRNA，在前期工作基础上，以KIT表达阳性GIST为研究对象，深入探讨上述miRNA的功能及其作用机制；研究候选miRNA对GIST预后的临床评估价值；并鉴定以上miRNA对靶基因KIT表达的影响；同时探讨候选miRNA模拟物对GIST的潜在治疗作用，为发现GIST治疗的新靶点和干预方法提供实验和理论依据

胃肠道间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤，目前尚无能准确评估GIST预后的可靠指标，且经典药物伊马替尼（IM）的耐药已经成为目前GIST治疗的棘手问题，作为GIST肿瘤进展及靶向治疗的重要位点，KIT受体是研究的焦点。本研究围绕GIST的表观遗传学调控开展了系列研究，验证了部分miRNA与GIST病程进展的相关性及肿瘤生物学行为预测价值，通过体外实验验证候选miRNA对GIST细胞功能的影响；探索了miRNA结合纳米材料对GIST的影响；并开展了lncRNA H19/KIT/miR-193a-3p ceRNA网络调控在GIST中的研究。结果发现miR-193a-3p和miR-218在GIST中的下调与患者的预后存在显著关联，miR-193a-3p的表达下调与IM治疗疗效存在显著相关；miR-193a-3p miR-222和miR-218显著抑制GIST-T1细胞的增殖、迁移与侵袭能力，并显著促进GIST细胞凋亡及对IM敏感性；miR-218结合了纳米载体对肿瘤细胞具有更好的亲和力，可以用于肿瘤治疗，miR-218对KIT的结合与抑制作用可以通过荧光素酶载体证实；发现了lncRNA H19的表达与GIST进展有着紧密的联系且与部分KIT相互作用的miRNA存在网络调控，IM与miRNA及lncRNA H19干扰的联合应用，对于GIST有着更好的抑制作用，更进一步为临床IM耐药的棘手问题提供了可能的解决思路。本研究从非编码RNA及其网络调控的层面揭示了GIST生成进展的调控机制。为找到抑制GIST肿瘤进展及解决IM耐药提供了崭新的实验数据与理论基础。