Fibroblast growth factors 9 (FGF9) modulates cell proliferation, differentiation and motility for development and repair in normal cells. Abnormal activation of FGF9 signaling is associated with tumor progression in many cancers. Also, FGF9 may be an unfavorable prognostic indicator for non-small cell lung cancer patients. However, the effects and mechanisms of FGF9 in lung cancer remain elusive. In this study, we investigated the FGF9-induced effects and signal activation profiles in mouse Lewis lung carcinoma (LLC) in vitro and in vivo. Our results demonstrated that FGF9 significantly induced cell proliferation and epithelial-to-mesenchymal transition (EMT) phenomena (migration and invasion) in LLC cells. Mechanism-wise, FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13), and reduced the expression of E-cadherin. Moreover, in the allograft mouse model, intratumor injection of FGF9 to LLC-tumor bearing C57BL/6 mice enhanced LLC tumor growth which were the results of increased Ki67 expression and decreased cleaved caspase-3 expression compared to control groups. Furthermore, we have a novel finding that FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. In conclusion, FGF9 activated FAK, AKT, and ERK signaling through FGFR1 with induction of EMT to stimulate LLC tumorigenesis and hepatic metastasis. This novel FGF9/LLC allograft animal model may therefore be useful to study the mechanism of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis.

成纤维细胞生长因子 9 (FGF9) 调节细胞增殖、分化和运动，以促进正常细胞的发育和修复。FGF9 信号的异常激活与许多癌症的肿瘤进展有关。此外，FGF9 可能是非小细胞肺癌患者的不利预后指标。然而，FGF9 在肺癌中的作用和机制仍然难以捉摸。在这项研究中，我们在体外和体内研究了 FGF9 在小鼠路易斯肺癌 (LLC)中的诱导作用和信号激活谱. 我们的结果表明，FGF9 显着诱导 LLC 细胞中的细胞增殖和上皮间质转化 (EMT) 现象（迁移和侵袭）。机制方面，FGF9 与 FGFR1 相互作用并激活 FAK、AKT 和 ERK/MAPK 信号通路，诱导 EMT 关键蛋白（N-钙粘蛋白、波形蛋白、蜗牛、MMP2、MMP3 和 MMP13）的表达，并降低 E 的表达-钙粘蛋白。此外，在同种异体移植小鼠模型中，向携带 LLC 肿瘤的 C57BL/6 小鼠肿瘤内注射 FGF9 增强了 LLC 肿瘤生长，这是与对照组相比 Ki67 表达增加和裂解的 caspase-3 表达降低的结果。此外，我们有一个新发现，即 FGF9 促进皮下接种的 LLC 肿瘤的肝转移，并在肿瘤微环境中具有血管生成、EMT 和 M2-巨噬细胞浸润。总之，FGF9 通过 FGFR1 激活 FAK、AKT 和 ERK 信号传导并诱导 EMT，以刺激 LLC 肿瘤发生和肝转移。因此，这种新的 FGF9/LLC 同种异体移植动物模型可能有助于研究肝转移的机制，肝转移是肺癌远处器官转移患者的最差预后因素。