ALK阳性间变大细胞淋巴瘤 IGF-IR调控机制的研究

ALK阳性间变大细胞淋巴瘤（ALK+ ALCL）以化疗为主，虽然缓解率高，但仍有40%患者复发。在分子学水平，这类淋巴瘤存在NPM-ALK融合蛋白。近年来研究提示ALK+ ALCL细胞IGF-IR异常高表达，且和NPM-ALK相互作用，在肿瘤进展中起着非常重要的作用。但IGF-IR表达上调的机制尚未阐明。本项目旨在从转录后水平探索IGF-IR的调控机制，MicroRNAs和RNA结合蛋白是两类重要的转录后调节因子。研究目标：1 探索Hsa-let-7b和HuR(RNA结合蛋白)竞争性调控IGF-IR的表达；2分析淋巴瘤标本IGF-IR和Hsa-let-7b 的mRNA水平，分析与临床及生存时间的关系；3从体内外实验研究Hsa-let-7b和HuR siRNA抗肿瘤活性。本项目旨在探索该类淋巴瘤IGF-IR的调控机制，并进一步揭示其与淋巴瘤疾病进展和预后的关系，为开拓分子靶向干预提供思路。

ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL) is an aggressive type of malignant lymphoma. It is currently based on the CHOP combination chemotherapy regimen. After an initial response to CHOP, around 40% of the patients develop resistance and have a relapse. At the molecular level, NPM-ALK+ ALCL is characterized by the expression of the chimeric tyrosine kinase NPM-ALK, which induces significant oncogenic effects through interactions with downstream molecules that promote lymphoma cell survival. We have demonstrated that IGF-1R play an important roles in promoting the survival of the ALK+ ALCL cells by interaction with NPM-ALK. However, the mechanisms that contribute to the aberrant expression of IGF-1R in ALK+ALCL are not completely understood. Here, we focus on post-transcriptional regulation of IGF-1R. RNA-binding proteins (RBPs) and microRNAs (miRNAs) are potent post-transcriptional regulators of gene expression, acting primarily through 5’ and 3’ untranslated regions (UTRs). Our specific aims are to investigate the regulating mechanism of IGF-1R expression by hsa-let-7b and HuR; To investigate the clinicopathologic correlation of hsa-let-7b and HuR and to identify the in vitro and in vivo preclinical effects of has-let-7 and HuR siRNA in ALK+ ALCL. Our project will provide insight into the regulation of IGF-1R expression by hsa-let-7b and HuR in in ALK+ ALCL. Our final aim is to understand IGF-IR-dependent signaling in this aggressive lymphoma in order to develop novel, targeted and safer therapeutic strategies.