基于细胞“失巢凋亡抵抗”途径探讨FASN促进骨肉瘤侵袭转移的新机制

Our previous studies showed that elevated expression of FASN promotes osteosarcoma (OS) cells invasion and metastasis, the mechanism of which gets partially involved in modulating HER2/PI3K/Akt signaling pathway. However, we also found that it was hard to explain the activation of HER2/PI3K/Akt signaling by FASN, facilitating OS cells metastasis. Obviously, there are theory significance and applied value to explore new molecular and cellular mechanisms of FASN which promotes cell metastasis in OS. Therefore, based on the previous work, we will apply a series of molecular genetics and biology methods in this study to explore the elevated expression of FASN promoting osteosarcom metastasis by mediating “anoikis resistance” in vitro and vivo. Futhermore, we will investgate whether FASN mediates cell “anoikis resistance” via activating ERK1/2/NF-κβ/Bcl-2 signaling pathway. Given the study was completed successfully, new cellular and molecular mechanisms of increased FASN expression enhancing OS cells metastasis would be enriched, and the new therapeutic strategies and intervening target would be provided for prevention and treatment of OS metastasis.

在前一国家自然科学基金项目的资助下我们证实：FASN参与骨肉瘤侵袭转移，其机制与HER2/PI3K/Akt通路有关。但FASN介导骨肉瘤侵袭转移难以完全用HER2/PI3K/Akt通路的激活来解释。显然，寻找FASN介导骨肉瘤侵袭转移的其它机制和靶点具有十分重要的理论意义和应用价值。为此，本研究拟在前期工作的基础上，从细胞和整体水平，利用一系列分子生物学实验手段，从FASN介导细胞“失巢凋亡抵抗”的角度，进一步阐明FASN介导骨肉瘤侵袭转移的新途径；同时，从ERK1/2/NF-κβ/Bcl-2信号通路进一步研究FASN介导“失巢凋亡抵抗”的分子机制。本研究的顺利完成将进一步丰富FASN促进骨肉瘤侵袭转移的机制，也将为骨肉瘤侵袭转移的防治提供新思路和新的干预环节。

骨肉瘤作为好发于儿童及青少年中最具侵袭性的原发性骨恶性肿瘤，肺部转移是患者死亡最主要的原因。在前一国家自然科学基金项目的资助下我们证实：FASN参与骨肉瘤侵袭转移，其机制与HER2/PI3K/Akt通路有关。但FASN介导骨肉瘤侵袭转移难以完全用HER2/PI3K/Akt通路的激活来解释。因此，为寻找FASN介导骨肉瘤侵袭转移的其它机制和靶点，我们开展了本项目的研究。本研究中我们发现：（1）FASN高表达介导骨肉瘤细胞“失巢凋亡抵抗”而促进骨肉瘤增殖和转移；（2）FASN部分通过激活ERK1/2/BCL-xl通路促进骨肉瘤细胞“失巢凋亡抵抗”而促进其增殖和转移；（3）体内研究进一步证实FASN部分通过促进ERK1/2/BCL-xl通路促进骨肉瘤细胞“失巢凋亡抵抗”而促进其增殖和转移。本研究首次揭示FASN通过介导“失巢凋亡抵抗”促进骨肉瘤肺转移及其分子机制，为今后进一步研究FASN作为肿瘤肺部转移靶点奠定基础。