@Article{or.2025.072084,
AUTHOR = {Xiaoyu Zhang, RenFei Zong, Yan Sun, Nan Chen, Kunyao Zhu, Hang Tong, Tinghao Li, Junlong Zhu, Zijia Qin, Linfeng Wu, Aimin Wang, Weiyang He},
TITLE = {The FN1-ITGB4 Axis Drives Acquired Chemoresistance in Bladder Cancer by Activating FAK Signaling},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {2},
PAGES = {--},
URL = {http://www.techscience.com/or/v34n2/65589},
ISSN = {1555-3906},
ABSTRACT = { <b>Objective:</b> 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. <b>Methods:</b> 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 <i>in vivo</i>. <b>Results:</b> Integrated transcriptomic and proteomic analysis identified FN1 (fibronectin) as a consistently upregulated top candidate in resistant cells (T24-R transcript log<sub>2</sub>FC = 2.8, protein log<sub>2</sub>FC = 0.9; UC3-R transcript log<sub>2</sub>FC = 3.7; all <i>p</i> &lt; 0.001). Knockdown of FN1 reduced chemoresistance (Resistance Index: 5.2 in T24-R and 2.0 in UC3-R cells, <i>p</i> &lt; 0.001) and enhanced apoptosis (approximately 4.5-fold in T24-R and 7.5-fold in UC3-R, <i>p</i> &lt; 0.001). ITGB4 (Integrin Subunit Beta 4) was upregulated in resistant cells (transcript log<sub>2</sub>FC: 4.2 in T24-R and 3.03 in UC3-R; protein log<sub>2</sub>FC: 0.67 in T24-R; all <i>p</i> &lt; 0.01). Critically, ITGB4 knockdown abolished the chemoresistance promoted by exogenous FN1, which was associated with increased FAK (Y397) phosphorylation. <b>Conclusion:</b> 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.},
DOI = {10.32604/or.2025.072084}
}