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Abstract：
Angiosarcoma is a rare refractory soft-tissue tumor with a poor prognosis and is treated by radiotherapy. The fibroblast growth factor 1 (FGF1) mutant, with enhanced thermostability due to several substituted amino acids, inhibits angiosarcoma cell metastasis, yet the mechanism of action is unclear. This study aims to clarify the FGF1 mutant mechanism of action using ISOS-1 mouse angiosarcoma cells. The wild-type FGF1 or FGF1 mutant was added to ISOS-1 cells and cultured, evaluating cell numbers over time. The invasive and migratory capacity of ISOS-1 cells was assessed by transwell analysis. ISOS-1 cell radiosensitivity was assessed by colony formation assay after X-ray irradiation. To examine whether mitogen-activated protein kinase (MEK) inhibitor counteracts the FGF1 mutant effects, a combination of MEK inhibitor and FGF1 mutant was added to ISOS-1 cells and cultured. The FGF1 mutant was observed to inhibit ISOS-1 cell proliferation, invasion and migration by sustained FGF1 signaling activation. A MEK inhibitor suppressed the FGF1 mutant-induced inhibition of proliferation, invasion and migration of ISOS-1 cells. Furthermore, the FGF1 mutant enhanced radiosensitivity of ISOS-1 cells, but MEK inhibition suppressed the increased radiosensitivity. In addition, we found that the FGF1 mutant strongly inhibits actin polymerization, suggesting that actin cytoskeletal dynamics are closely related to ISOS-1 cell radiosensitivity. Overall, this study demonstrated that in ISOS-1 cells, the FGF1 mutant inhibits proliferation, invasion and migration while enhancing radiosensitivity through sustained activation of the MEK-mediated signaling pathway.
摘要：
血管肉瘤是一种罕见的难治性软组织肿瘤，预后差，可通过放射治疗进行治疗。成纤维细胞生长因子1（FGF1）突变体，由于几个取代的氨基酸，具有增强的热稳定性，抑制血管肉瘤细胞转移，然而，作用机制尚不清楚。本研究旨在阐明使用ISOS-1小鼠血管肉瘤细胞的FGF1突变体的作用机制。将野生型FGF1或FGF1突变体添加到ISOS-1细胞中进行培养,随着时间的推移评估细胞数量。通过transwell分析评估ISOS-1细胞的侵袭和迁移能力。通过X射线照射后的集落形成测定来评估ISOS-1细胞的放射敏感性。为了检查丝裂原活化蛋白激酶（MEK）抑制剂是否抵消FGF1突变体的作用，将MEK抑制剂和FGF1突变体的组合加入ISOS-1细胞并培养.观察到FGF1突变体抑制ISOS-1细胞增殖,通过持续的FGF1信号激活进行入侵和迁移。MEK抑制剂抑制FGF1突变体诱导的增殖抑制，ISOS-1细胞的侵袭和迁移。此外，FGF1突变体增强了ISOS-1细胞的放射敏感性，但是MEK抑制抑制了放射敏感性的增加。此外,我们发现FGF1突变体强烈抑制肌动蛋白聚合，提示肌动蛋白细胞骨架动力学与ISOS-1细胞放射敏感性密切相关。总的来说,这项研究表明，在ISOS-1细胞中，FGF1突变体抑制增殖，侵袭和迁移，同时通过持续激活MEK介导的信号通路增强放射敏感性。
