LAMC2/Akt信号通路在骨肉瘤细胞失巢凋亡与肺转移中的作用

Osteosarcoma is the most common primary malignant tumor of bone. Though treated by combined therapy, the prognosis of osteosarcoma is poor. Pulmonary metastasis is the main reason caused the death of osteosarcoma patients. Recent studies showed anoikis played an important role during cancer metastasis and Akt pathway played a crucial regulation role. Our preliminary studies haved showed the new subtype osteosarcoma cells separated from the pulmonary metastases of nude mouse manifested conspicuous anoikis resistance with sustained Akt activation; Microarray analysis have found positive regulation relation between LAMC2 and Akt; PCR and Western blot have testified upregulation of LAMC2 in the subtype osteosarcoma cells. This study hopes testifying LAMC2 activate Akt pathway which result in anoikis resistance and pulmonary metastasis in osteosarcoma. The total studies are as follows: in vivo study based on in vivo imaging technology and dual luciferase labeling; mechanism of LAMC2/Akt pathway in anoikis and pulmonary metastasis of osteosarcoma; correlation studies between LAMC2 expression and life span/turnover in osteosarcoma patients.

骨肉瘤是最常见的原发恶性肿瘤，目前尽管经过综合治疗，患者预后仍然不好，而骨肉瘤肺转移是导致患者死亡的主要原因。近期研究表明，失巢凋亡在肿瘤转移中发挥重要作用，Akt通路在其中扮演关键调控角色。前期研究表明，从模型动物肺转移灶中分离出的高转移潜能骨肉瘤细胞亚群具有显著抵抗失巢凋亡的能力并伴Akt信号分子持续激活；基因芯片分析提示LAMC2高表达与Akt激活存在正向调控关系；PCR及Western blot证实LAMC2在高转移潜能骨肉瘤细胞亚群中表达上调。本研究拟通过小动物活体成像技术在体观察、基因过表达、基因沉默及免疫共沉淀等分子生物学手段，明确LAMC2/Akt信号通路在骨肉瘤细胞失巢凋亡及肺转移中的作用机制，同时测定临床标本LAMC2蛋白的表达，结合患者生存期及临床转归情况进行分析，证明LAMC2激活Akt通路促使骨肉瘤细胞逃避失巢凋亡进而发生肺转移。

骨肉瘤是最常见的原发恶性肿瘤，目前尽管经过综合治疗，患者预后仍然不好，而骨肉瘤肺转移是导致患者死亡的主要原因。本研究通过基因过表达、基因沉默等分子生物学手段，明确了LAMC2/Akt信号通路激活在骨肉瘤细胞逃避失巢凋亡并促进其肺转移中的作用。