Gankyrin调控Hippo信号通路在骨肉瘤发生发展中的作用及机制研究

Osteosarcoma is a common primary malignancy of bone in children and adolescents, the mechanism of the occurrence and development is not clear. Although oncogene Gankyrin is involved in the occurrence and development of some tumor, the role and mechanism of Gankyrin in osteosarcoma still remains unclear. Our preliminary studies showed Gankyrin was overexpressed in osteosarcoma tissues, it indicated that Gankyrin expression was associated with the occurrence and development of osteosarcoma. Further studies revealed that Gankyrin interacted with LATS1, which is a upstream regulator of Hippo signaling pathway. Moreover, Gankyrin promoted the degradation of LATS1 and changed the level of target genes in Hippo/YAP signaling pathway. It indicated that Gankyrin may bind with LATS1 and promote the degradation of LATS1, then suppress the phosphorylation of YAP and promote the nuclear translocation of YAP. Furthermore, the target genes in Hippo/YAP signaling are activated and occurrence and development of osteosarcoma is promoted. Therefore, this study intends to observe the correlation between Gankyrin and prognosis or metastasis of osteosarcoma, explore the effect and mechanism of Gankyrin on occurrence and development of osteosarcoma through regulating Hippo signaling pathway. So as to provide new ideas and exprimental evidence for the effective treatment of osteosarcoma.

骨肉瘤是儿童和青少年最常见的原发恶性骨肿瘤，发生发展的机制不明。研究表明癌基因Gankyrin在部分肿瘤发生发展中起重要作用，但在骨肉瘤中的作用及机制不清。我们前期研究发现Gankyrin在骨肉瘤组织中呈高表达，提示它可能与骨肉瘤的发生发展密切相关。进一步研究发现Gankyrin可与Hippo信号通路上游调节分子LATS1相互作用，且两者表达呈负相关，同时Gankyrin可引起Hippo/YAP信号通路下游靶基因表达变化，提示Gankyrin可能通过与LATS1结合并促进其降解，从而抑制YAP的磷酸化，促进YAP入核而使下游靶基因转录，影响骨肉瘤的发生发展。本研究拟分别从分子、细胞、组织以及动物水平，研究Gankyrin与骨肉瘤预后、转移的相关性及其对骨肉瘤发生发展的影响，并阐明Gankyrin调控Hippo信号通路参与骨肉瘤发生发展的具体分子机制，为有效治疗骨肉瘤提供新思路和实验依据。

骨肉瘤是儿童和青少年最常见的原发恶性骨肿瘤，发生发展的机制不明。Gankyrin是一个近年来新发现的癌蛋白，属于锚蛋白家族成员，在骨肉瘤中的作用及机制不清。Hippo信号通路是当前的研究热点之一，其失调会引起肿瘤的发生和发展，YAP蛋白为该信号通路核心效应分子。本研究发现Gankyrin在骨肉瘤细胞系和组织中高表达，且Gankyrin的高表达与骨肉瘤患者的不良预后密切相关。Gankyrin可以促进骨肉瘤细胞增殖、侵袭和转移，机制上，Gankyrin可以通过P53阻碍miR-200a介导的YAP表达下调，反之，YAP可以上调Gankyrin表达从而形成正反馈调节。Gankyrin通过与YAP相互作用促进骨肉瘤生长，且Gankyrin和YAP在骨肉瘤组织标本中表达具有相关性。本项目为有效治疗骨肉瘤提供了新的思路和实验依据。