@article{Zhang2026, 
author = {Xiaoyu Zhang and RenFei Zong and Yan Sun and Nan Chen and Kunyao Zhu and Hang Tong and Tinghao Li and Junlong Zhu and Zijia Qin and Linfeng Wu and Aimin Wang and Weiyang He},
title = {The FN1-ITGB4 Axis Drives Acquired Chemoresistance in Bladder Cancer by Activating FAK Signaling},
year = {2026},
journal = {Oncology Research},
volume = {34},
number = {2},
pages = {21},
keywords = {Bladder cancer, chemoresistance, fibronectin, focal adhesion kinase, integrin subunit beta 4, gemcitabine and cisplatin},
url = {https://www.sciopen.com/article/10.32604/or.2025.072084},
doi = {10.32604/or.2025.072084},
abstract = {ObjectiveWhile 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.MethodsWe 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.ResultsIntegrated 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.ConclusionOur 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.}
}