ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer

Background: Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder Cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear.

Methods: We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative Real-Time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance.

Results: In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial-mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC.

Conclusion: Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC.

ADAM12; Bladder cancer; EGFR; EMT; Gemcitabine resistance.