Abstract:
Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn\'t alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.
摘要:
胃肠道间质瘤(GIST)主要由KIT突变体诱导。在这项研究中,我们发现4个半LIM结构域2(FHL2)在GIST中高表达,KIT信号显著增加FHL2转录,而FHL2抑制KIT转录.此外,我们的结果表明,FHL2与KIT相关,并增加了GIST中野生型KIT和初级KIT突变体的泛素化,尽管与野生型KIT相比,初级KIT突变体受FHL2的抑制较少,但导致KIT的表达和激活降低。在动物实验中,FHL2表达的缺失在携带种系KIT/V558A突变的小鼠中,该突变可以发展GIST导致肿瘤生长增加,但GIST对伊马替尼治疗的敏感性增加,伊马替尼被用作GIST的一线靶向治疗,提示FHL2在GIST对KIT抑制剂的反应中起作用。与野生型KIT和初级KIT突变体不同,我们进一步发现FHL2并没有改变耐药二级KIT突变体的表达和激活。一起来看,我们的结果表明,FHL2在GIST中充当KIT信号的负反馈,而初级KIT突变体敏感性较低,而次级KIT突变体对FHL2的抑制具有抗性。