Li Yiming, Liang Jianshen, Ren Xiude, Guo Jiahe, Wang Xisen, Wang Xuya, Yu Shengping, Li Tao, Yang Xuejun
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Laboratory of Neuro-Oncology, Tianjin Medical University General Hospital, Tianjin, China.
Front Oncol. 2025 Apr 8;15:1560008. doi: 10.3389/fonc.2025.1560008. eCollection 2025.
The Fibroblast growth factor receptors 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3, F3-T3) oncogenic fusion gene, identified in malignant tumors such as gliomas and bladder cancer, has been particularly noted in recurrent gliomas where it is considered to drive malignant progression, thus presenting itself as a viable therapeutic target. However, the precise mechanism by which F3-T3 facilitates the malignant progression of glioma is not fully understood.
Correction analysis of STAT3 and FGFR3 with major glioma mutation types and pan-cancer analysis was conducted using The Cancer Genome Atlas (TCGA) database. A series of phenotypic experiments, including CCK-8, EdU, colony-formation assay, wound healing assay, and transwell assay were conducted to detect the effects of F3-T3 on proliferation, invasion, and migration of glioma cells. The association between F3-T3 and epithelial-mesenchymal transition (EMT) was investigated through enrichment analysis of the E-MTAB-6037 gene chip database and confirmed by western blot. The underling mechanism were further inferred and validated through RNA sequencing, E-MTAB-6037 gene chip data, and western blot. The relationship between p-STAT3 expression and the WHO grade of glioma was evaluated using immunohistochemistry (IHC) and tissue microarray analysis. Furthermore, the results of vivo experiments and IHC has confirmed the impact of F3-T3 on glioma malignant progression and activation of the STAT3 signaling pathway.
The experimental results from this study indicate that F3-T3 accelerates the epithelial-mesenchymal transition (EMT) process in glioma cells, thereby promoting their proliferation, invasion, and migration capabilities. Mechanistically, it was determined through RNA sequencing that the signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for the malignant progression of F3-T3. This finding was further supported through follow-up experiments conducted after STAT3 knockdown. The role of the STAT3 pathway in gliomas was also reinforced through bioinformatic analysis and immunohistochemistry (IHC) on tissue microarrays (TMA). Further experiments corroborated the role of F3-T3 in enhancing glioma growth and progression.
F3-T3 facilitates the proliferation, invasion, migration and EMT of glioma cells, thereby promoting their malignant progression through STAT3 signaling activation. These findings highlight its potential as a therapeutic target for glioma treatment.
成纤维细胞生长因子受体3-转化酸性卷曲螺旋蛋白3（FGFR3-TACC3，F3-T3）致癌融合基因在胶质瘤和膀胱癌等恶性肿瘤中被发现，在复发性胶质瘤中尤为显著，被认为可驱动恶性进展，因此是一个可行的治疗靶点。然而，F3-T3促进胶质瘤恶性进展的确切机制尚不完全清楚。
使用癌症基因组图谱（TCGA）数据库对STAT3和FGFR3与主要胶质瘤突变类型进行校正分析，并进行泛癌分析。进行了一系列表型实验，包括CCK-8、EdU、集落形成实验、伤口愈合实验和transwell实验，以检测F3-T3对胶质瘤细胞增殖、侵袭和迁移的影响。通过E-MTAB-6037基因芯片数据库的富集分析研究F3-T3与上皮-间质转化（EMT）之间的关联，并通过蛋白质免疫印迹法进行验证。通过RNA测序、E-MTAB-6037基因芯片数据和蛋白质免疫印迹法进一步推断和验证潜在机制。使用免疫组织化学（IHC）和组织芯片分析评估p-STAT3表达与胶质瘤WHO分级之间的关系。此外，体内实验和IHC的结果证实了F3-T3对胶质瘤恶性进展和STAT3信号通路激活的影响。
本研究的实验结果表明，F3-T3加速了胶质瘤细胞的上皮-间质转化（EMT）过程，从而促进了它们的增殖、侵袭和迁移能力。机制上，通过RNA测序确定转录信号转导子和激活子3（STAT3）信号通路对F3-T3的恶性进展至关重要。STAT3基因敲低后进行的后续实验进一步支持了这一发现。通过生物信息学分析和组织芯片（TMA）上的免疫组织化学（IHC）也加强了STAT3通路在胶质瘤中的作用。进一步的实验证实了F3-T3在促进胶质瘤生长和进展中的作用。
F3-T3促进胶质瘤细胞的增殖、侵袭、迁移和EMT，从而通过激活STAT3信号促进其恶性进展。这些发现突出了其作为胶质瘤治疗靶点的潜力。
