Abstract
Although intravesical gemcitabine (GEM) chemotherapy (IGC) can effectively reduce the recurrence risk of non-muscle invasive bladder cancer (NMIBC), the development of GEM resistance may occur and result in cancer recurrence and disease progression. Herein, a label-free proteomics approach was used to characterize the proteomic profiles of primary/post-IGC recurrent NMIBC. A total of 218 proteins were found to be differentially expressed in paired primary and post-IGC recurrent NMIBC. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that multiple signaling pathways including "focal adhesion" were highly enriched in recurrent NMIBC. Niban apoptosis regulator 1 (NIBAN1) was identified as the top upregulated protein in recurrent NMIBC. Highly increased NIBAN1 expression was observed in a number of GEM-resistant cancer cell lines and in post-IGC recurrent NMIBC specimens. Manipulation of NIBAN1 expression affected the chemosensitivity to GEM in bladder cancer cell models. Moreover, NIBAN1 also regulated focal adhesion/focal adhesion kinase (FAK) signaling activation in bladder cancer cell lines. Highly elevated FAK (pY397) expression was observed in post-IGC recurrent NMIBC specimens, which was positively correlated with NIBAN1 expression. Knockdown of FAK markedly attenuated GEM resistance in GEM-resistant bladder cancer cells. In vivo studies demonstrated that knockdown of NIBAN1 disrupted FAK signaling and sensitized GEM-resistant bladder cancer cells to GEM treatment. Our findings suggest that NIBAN1 might regulate FAK signaling activation to promote GEM resistance in bladder cancer. Targeting NIBAN1/FAK signaling may help sensitize bladder cancer cells to GEM treatment.