FASN调控HER2/PI3K/AKT/NF-κB通路促进骨肉瘤侵袭转移

Osteosarcoma(OS) is the most common primary malignant bone tumour in children and adolescents. The development of lung metastasis is the main cause of death in patients with OS. Therefore the underlying molecular mechanism of metastasis is one of the hotspots for treating osteosarcoma. In recent years, studies show that FASN may be closely related with tumor metastasis. In our previous studies we found that FASN expression in OS tissues with lung metastasis was obviously higher than in those without lung metastasis, and that inhibition of FASN can significantly result in reduction of U2-OS cell migration and invasion, which suggests that FASN may be closely related with metastasis of osteosarcoma. However, whether FASN takes a role in OS metastasis and what is the mechanism is not yet clear. In this study, the effect of FASN expression on OS cell invasion and lung metastasis will be investigated in OS cell line and nude mice, also the effect of FASN expression on expression of HER2/PI3K/AKT/NF-kB signal pathway will be studied, based on which some molecules can be used as new targets in prevetion and treatment of OS metastasis.

骨肉瘤在青少年和儿童原发恶性骨肿瘤中占据首位，肺部转移是骨肉瘤患者死亡最主要原因，因此阐明骨肉瘤转移分子机制是骨肉瘤防治研究的热点之一。近来研究表明FASN(Fatty Acid Synthase) 可能与肿瘤转移密切相关。我们前期工作发现FASN在有肺转移的骨肉瘤组织中表达明显高于无肺转移的骨肉瘤组织；同时发现FASN抑制剂cerulenin能明显降低U2OS细胞的迁徙、侵袭力。提示FASN可能与骨肉瘤转移密切相关，但FASN是否直接参与骨肉瘤侵袭转移及相关分子机制有待于进一步明确。为此本研究拟在细胞及整体水平，应用基因转染、RNA干扰等分子生物学手段观察FASN表达水平对骨肉瘤细胞侵袭和肺部转移的影响，以期阐明FASN是否直接参与骨肉瘤转移；同时从HER2/PI3K/AKT/NF-KB信号的角度进一步探讨FASN促骨肉瘤侵袭转移的分子机制。本研究将为骨肉瘤转移的的防治提供新的分子靶点。

骨肉瘤是好发于儿童和青少年的一种恶性骨肿瘤，约占恶性骨肿瘤的35%。近几十年来全球的骨肉瘤患者总体5年生存率仍然徘徊不前，肺部转移是骨肉瘤患者目前最主要的死亡原因。因此，骨肉瘤转移相关分子机制的探讨成为骨肉瘤研究领域的重点和热点之一，对诊治和预防骨肉瘤侵袭转移和提高生存率具有重大意义。本研究中我们发现：（1））FASN蛋白在骨肉瘤组织中呈高表达，并且其表达水平与骨肉瘤肺部转移密切相关；（2））FASN高表达激活HER2/PI3K/AKT/NF-κβ信号通路促进骨肉瘤细胞侵袭转移；（3）FASN 与 HER2、FASN与PI3K/Akt通路在骨肉瘤细胞中存在正反馈调节；（4））FASN是miR-195/424的靶基因，miR-195/424能负向调控FASN而抑制骨肉细胞迁移和侵袭能力；（5）外源性基因NF-YA作用于FASN启动子区来上调FASN在骨肉瘤细胞中的表达促进细胞侵袭迁徙。FASN在代谢途径中起着非常关键的作用，负责肿瘤细胞中脂肪酸的合成。