Open Access
ARTICLE
The FN1-ITGB4 Axis Drives Acquired Chemoresistance in Bladder Cancer by Activating FAK Signaling
Xiaoyu Zhang1,#, RenFei Zong1,#, Yan Sun1, Nan Chen2, Kunyao Zhu1, Hang Tong1, Tinghao Li1, Junlong Zhu1, Zijia Qin1, Linfeng Wu1, Aimin Wang1, Weiyang He1,*
1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
2 Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
* Corresponding Author: Weiyang He. Email: 
# These authors contributed equally to this work
(This article belongs to the Special Issue: Signaling Pathway Crosstalk in Malignant Tumors: Molecular Targets and Combinatorial Therapeutics)
Oncology Research https://doi.org/10.32604/or.2025.072084
Received 19 August 2025; Accepted 12 November 2025; Published online 11 December 2025
Abstract
Objective: While cisplatin-based chemotherapy is pivotal for advanced bladder cancer, acquired resistance remains a major obstacle. This study investigates key molecular drivers of this resistance and potential reversal strategies. Methods: We established GC (Gemcitabine and Cisplatin)-resistant T24-R and UC3-R cell lines from T24 and UM-UC-3 (UC3) cells. Transcriptomic and proteomic analyses identified differentially expressed molecules. Apoptosis and cell viability were assessed by flow cytometry and CCK-8 (Cell Counting Kit-8) assays, while RT-qPCR (Reverse Transcription Quantitative Polymerase Chain Reaction) and Western blot analyzed gene and protein expression. Immunofluorescence evaluated FAK (Focal Adhesion Kinase) phosphorylation, and a xenograft mouse model validated the findings in vivo. Results: Integrated transcriptomic and proteomic analysis identified FN1 (fibronectin) as a consistently upregulated top candidate in resistant cells (T24-R transcript log2FC = 2.8, protein log2FC = 0.9; UC3-R transcript log2FC = 3.7; all p < 0.001). Knockdown of FN1 reduced chemoresistance (Resistance Index: 5.2 in T24-R and 2.0 in UC3-R cells, p < 0.001) and enhanced apoptosis (approximately 4.5-fold in T24-R and 7.5-fold in UC3-R, p < 0.001). ITGB4 (Integrin Subunit Beta 4) was upregulated in resistant cells (transcript log2FC: 4.2 in T24-R and 3.03 in UC3-R; protein log2FC: 0.67 in T24-R; all p < 0.01). Critically, ITGB4 knockdown abolished the chemoresistance promoted by exogenous FN1, which was associated with increased FAK (Y397) phosphorylation. Conclusion: Our results demonstrate that the FN1-ITGB4 axis drives chemoresistance in bladder cancer via FAK signaling. Targeting this axis represents a promising strategy to overcome chemoresistance.
Keywords
Bladder cancer; chemoresistance; fibronectin; focal adhesion kinase; integrin subunit beta 4; gemcitabine and cisplatin
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