miR-429-CRKL axis通过Raf/MEK/ERK通路调控白血病细胞红系分化的作用机制研究

miR-429异常表达与肿瘤密切相关，但miR-429与红系分化相关性研究未见报道。本组前期发现：miR-429靶向CRKL通过Raf/MEK/ERK-EMT通路影响肝癌HepG2细胞迁移、侵袭；CRKL通过Raf/MEK/ERK通路影响K562细胞红系分化；miR-429、CRKL在肝/血癌样本中表达呈明显负相关；miR-429在K562细胞红系分化过程中表达升高。我们推测miR-429靶向CRKL通过Raf/MEK/ERK通路调控白血病细胞红系分化。本课题拟阐明miR-429、CRKL对K562、HEL、CD34+细胞红系分化的影响及相互作用；明确miR-429通过抑制CRKL调控红系分化；揭示miR-429-CRKL axis通过Raf/MEK/ERK通路调控红系分化的作用机制；探讨miR-429对小鼠体内造血干细胞及白血病细胞红系分化的影响，为白血病分子靶向治疗提供新线索和新思路。

miR-429 dysregulation is closely related with tumor, however, its association with erythroid differentiation has not been reported. Previous work from our group indicated that: miR-429 regulated hepatocarcinoma HepG2 cell migration and invasion by targeting CRKL via Raf/MEK/ ERK-EMT pathway; CRKL regulated K562 cell erythroid differentiation via Raf/MEK/ERK pathway; miR-429 expression was negatively correlated with CRKL expression in liver caner/leukemia patient samples; miR-429 expression level was upregulated during erythroid differentiation of K562 cell. We speculate miR-429 regulates leukemia cell erythroid differentiation by targeting CRKL via Raf/MEK/ERK pathway. This proposal aims to clarify the effects and mutual responding mechanism of miR-429 and CRKL on erythroid differentiation of leukemia K562, HEL cells and CD34+ hematopoietic stem cell; to demonstrate miR-429 regulates erythroid differentiation by inhibiting CRKL expression; to reveal the action mechanism of miR-429-CRKL axis mediates erythroid differentiation via Raf/MEK/ERK pathway; to explore the effect of miR-429 on erythroid differentiation of mouse hematopoietic stem cell and leukemia cell in vivo. The current proposal will provide novel insights and clues into leukemia targeting therapy.