全反式维甲酸调控miR-34a-E2F1/3-Eag1信号通路抑制骨肉瘤恶性表型的研究

In recent years, ether à go-go 1 (Eag1) has been considered as a novel oncogene and therapeutic target for cancers. However, the mechanisms underlying the contribution of Eag1 to tumorigenesis and its therapeutic potential in osteosarcoma remained unexplored. . Interestingly, previous studies including ours have shown that miR-34a was downregulated while Eag1 was aberrantly expressed in osteosarcoma. E2F1 and E2F3, the target genes of miR-34a, are transactivators of Eag1. Inhibition of Eag1 can inhibit tumor growth and promot osteogenic differentiation in osteosarcoma. All-trans retinoic acid (ATRA) has been shown to induce osteogenic differentiation and the expression of miR-34a, suppress malignant phenotypes and the expression of Eag1 in osteosarcoma. Therefore, we put forward our hypothesis that ATRA activates the miR-34a-E2F1/3-Eag1 pathway to exhibit anti-tumor activity against osteosarcoma. . To confirm our hypothesis, the existence of miR-34a-E2F1/3-Eag1 pathway in osteosarcoma will be confirmed firstly. Then the malignant phenotypes and the expression of miR-34a, E2F1, E2F3 and Eag1 in osteosarcoma cells and xenografts will be detected after treated with different concentrations of ATRA. Based on the results above, the malignant phenotypes of osteosarcoma will be examined again after intervention of the pathway or combine with ATRA treatment. It is expected that we will help elucidate new signaling mechanism by which Eag1 contributes to tumorigenesis and ATRA exhibits anti-tumor effects on osteosarcoma and provide a novel thought and therapeutic target for the prevention and treatment of osteosarcoma.

Eag1是新近发现的癌基因和肿瘤治疗靶点，但在骨肉瘤中致癌机制和治疗作用尚未明确。我们前期及既往研究表明：①下调Eag1表达可抑制骨肉瘤增殖并诱导骨向分化；②骨肉瘤中miR-34a表达下调，其靶基因E2F1和E2F3是Eag1的转录因子；③ATRA可抑制骨肉瘤恶性表型和Eag1表达，诱导骨向分化和miR-34a表达。据此我们推测：ATRA通过激活miR-34a-E2F1/3-Eag1信号通路抑制骨肉瘤恶性表型。本项目拟首先证实骨肉瘤中存在上述信号通路，之后观察不同浓度ATRA处理对骨肉瘤恶性表型的影响，同时检测miR-34a、E2F1、E2F3和Eag1表达。在此基础上，干预该信号通路或联合ATRA处理，观察上述处理对骨肉瘤恶性表型的影响，初步阐明该信号通路在促骨肉瘤恶性表型和ATRA抗骨肉瘤中的作用。本项目有助于揭示Eag1致癌和ATRA抗骨肉瘤的机制，为骨肉瘤防治提供新思路和治疗靶点。

Eag1是新近发现的癌基因和肿瘤治疗靶点，但在骨肉瘤中致癌机制和治疗作用尚未明确。本项目拟首先证实骨肉瘤中存在上述信号通路，之后观察不同浓度ATRA处理对骨肉瘤恶性表型的影响，同时检测miR-34a、E2F1、E2F3和Eag1表达。在此基础上，干预该信号通路或联合ATRA处理，观察上述处理对骨肉瘤恶性表型的影响，初步阐明该信号通路在促骨肉瘤恶性表型和ATRA抗骨肉瘤中的作用。研究结果发现：ATRA可有效地抑制骨肉瘤增殖、侵袭和迁移等恶性表型，其作用机制与miR-34a-E2F1/3-Eag1信号通路有关。此外的研究表明Erg1通道也参与了骨肉瘤恶性表型的调控中，具体的机制仍需进一步研究。本项目初步揭示Eag1和Erg1致癌和ATRA抗骨肉瘤的机制，为骨肉瘤防治提供新思路和治疗靶点。