miR-125b靶向调节HK2在骨肉瘤细胞糖酵解、增殖与转移中的作用及机制研究

Osteosarcoma is the most common primary malignant bone tumor in children and adolescent. Hexokinase 2 plays a critical role in glycolysis, which is associated with the tumor initiation and maintenance. Our previous studies have demonstrated that the expression of HK2 was elevated in osteosarcoma and the expression of miR-125b was down-regulated. Additionally MiR-125b decreased the protein levels of HK2 in osteosarcoma. Moreover miR-125b suppressed the proliferation and migration of osteosarcoma cells. Bioinformatics tools found there is highly conserved sequence in the 3’-untanslated region (UTR) of HK2 capable of pairing to miR-125b, which suggest that miR-125b may regulate glycolysis to inhibit proliferation and migration of osteosarcoma cells via targeting HK2. Based on our previous findings, this project is to establish the relationship between miR-125b-HK2 expressions and the pathological grade and treatment effect of osteosarcoma, and to further investigate the regulation of HK2 by miR-125b in glycolysis, proliferation and migration of osteosarcoma cells and its molecular mechanisms. This project would help elucidate the role of glycolysis in the occurrence and development of osteosarcoma, and hold potential for a new theoretical basis and new treatment targets of osteosarcoma.

骨肉瘤是青少年最常见的原发性恶性骨肿瘤。肿瘤的发生、发展与糖酵解异常活动密切相关，其中己糖激酶2（HK2）发挥着重要的作用。我们前期研究发现，HK2在骨肉瘤中表达水平升高，而miR-125b的表达水平降低；骨肉瘤细胞中过表达miR-125b能降低HK2的蛋白表达水平；miR-125b能明显抑制骨肉瘤增殖与迁移；生物信息学手段发现HK2的3’UTR区具有能够与miR-125b结合的高度保守序列。这提示miR-125b可能通过调节HK2介导肿瘤细胞的糖酵解从而抑制骨肉瘤细胞的增殖和迁移。本课题在前期研究的基础上，拟建立miR-125b-HK2表达水平与骨肉瘤病理分级、治疗效果之间的相关性，深入探讨miR-125b通过靶向调控HK2介导骨肉瘤细胞糖酵解、增殖和转移及其分子机制。本研究将有助于初步阐明糖酵解在骨肉瘤发生、发展中的作用，并有可能为骨肉瘤的发病机制提供新的理论依据和新的治疗靶点。

骨肉瘤是青少年最常见的原发性恶性骨肿瘤。肿瘤的发生、发展与糖酵解异常活动密切相关，其中己糖激酶2（HK2）发挥着重要的作用。我们发现，HK2表达水平在骨肉瘤组织中相对癌旁组织，骨肉瘤细胞系相对成骨细胞系均有上调。同时体外实验证实HK2能够促进骨肉瘤细胞的糖酵解、增殖、迁移和侵袭，生物信息学手段发现HK2的3’UTR区具有能够与miR-125b结合的高度保守序列。这提示miR-125b可能通过调节HK2介导肿瘤细胞的糖酵解从而抑制骨肉瘤细胞的增殖和迁移。通过萤光素酶实验，进一步明确了miR-125b直接靶向结合HK2的3’UTR区域。本项目中首先发现了miR-125b-HK2通路的存在，并证明其在骨肉瘤发生、发展中的作用机制。本研究将有助于初步阐明糖酵解在骨肉瘤发生、发展中的作用，并有可能为骨肉瘤的发病机制提供新的理论依据和新的治疗靶点。