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.

中文翻译：

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FGF1-MEK-ERK通路的持续激活抑制小鼠血管肉瘤细胞的增殖、侵袭和迁移并增强放射敏感性

血管肉瘤是一种罕见的难治性软组织肿瘤，预后较差，只能通过放射治疗来治疗。成纤维细胞生长因子 1 (FGF1) 突变体由于多个氨基酸取代而具有增强的热稳定性，可抑制血管肉瘤细胞转移，但作用机制尚不清楚。本研究旨在利用 ISOS-1 小鼠血管肉瘤细胞阐明 FGF1 突变体的作用机制。将野生型 FGF1 或 FGF1 突变体添加到 ISOS-1 细胞中并培养，评估随时间变化的细胞数量。通过 Transwell 分析评估 ISOS-1 细胞的侵袭和迁移能力。 X射线照射后通过集落形成测定评估ISOS-1细胞的放射敏感性。为了检查丝裂原激活蛋白激酶 (MEK) 抑制剂是否抵消 FGF1 突变体的影响，将 MEK 抑制剂和 FGF1 突变体的组合添加到 ISOS-1 细胞中并进行培养。观察到 FGF1 突变体通过持续的 FGF1 信号传导抑制 ISOS-1 细胞增殖、侵袭和迁移。 MEK 抑制剂可抑制 FGF1 突变体诱导的 ISOS-1 细胞增殖、侵袭和迁移的抑制作用。此外，FGF1突变体增强了ISOS-1细胞的放射敏感性，但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，表明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。总体而言，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 介导的信号通路来增强放射敏感性。