FGFR3-TACC3 fusion gene promotes glioblastoma malignant progression through the activation of STAT3 signaling pathway

Yiming Li ^1,2 Jianshen Liang ^1,2,3 Xiude Ren ^1,2 Jiahe Guo ^1,2,3 Xisen Wang ^1,2,3 Xuya Wang ^1,2,3 Shengping Yu ^1,2 Tao Li ^1,2 Xuejun Yang ^1,2,3*

• ¹ Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
• ² Laboratory of Neuro-oncology, Tianjin Medical University General Hospital, Tianjin, China
• ³ Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China

Objective: 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.Methods: Correction analysis of STAT3 and FGFR3 with major glioma mutation types and pancancer 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. Results: The experimental results from this study indicate that F3-T3 accelerates the epithelialmesenchymal 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 in vivo experiments corroborated the role of F3-T3 in enhancing glioma growth and progression. Conclusion: 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.