Laminin-integrin a6b4 interaction activates notch signaling to facilitate bladder cancer development

Background: Laminins are high-molecular weight (400 ~ 900 kDa) proteins in extracellular matrix, which serve as major component of the basal lamina, and play a crucial role in promoting tumor cell migration. This study aimed at characterizing the role of laminin in promoting Cancer development, and elucidating the mechanism of tumor progression driven by laminin-Notch signaling in bladder Cancer.

Methods: 2D collagen/laminin culture system was established and CCK-8/transwell assay was conducted to evaluate the proliferation/migration ability of Biu-87 and MB49 cells cultured on 2D gels. Activation of integrins-Notch1 signaling was determined by western blotting. Orthotopic bladder Cancer mice model was established to assess the therapeutic effects of Notch Inhibitor.

Results: Our study demonstrated that extracellular laminin can trigger tumor cell proliferation/migration through Integrin α6β4/Notch1 signaling in bladder Cancer. Inhibition of Telomere repeat-binding factor 3 (TRB3)/Jagged Canonical Notch Ligand 1 (JAG1) signaling suppressed Notch signals activation induced by laminin-integrin axis. In MB49 orthotopic bladder Cancer mice model, Notch Inhibitor SAHM1 efficiently improved tumor suppressive effects of chemotherapy and prolonged survival time of tumor-bearing mice.

Conclusion: In conclusion, we show that, in bladder Cancer, extracellular laminin induced the activation of Notch pathway through Integrin α6β4/TRB3/JAG3, and disclosed a novel role of laminin in bladder Cancer cells proliferation or migration.