Complement regulatory protein CD46 promotes bladder cancer metastasis through activation of MMP9

Abstract

CD46, a transmembrane protein known for protecting cells from complement-mediated damage, is frequently dysregulated in various types of cancer. Its overexpression in bladder cancers safeguards the cancer cells against both complement and antibody-mediated cytotoxicity. The present study explored a new role of CD46 in facilitating cancer cell invasion and metastasis, examining its regulatory effect on matrix metalloproteases (MMPs) and their effect on the metastatic capability of bladder cancer cells. Specifically, CD46 alteration positively influenced MMP9 expression, but not MMP2, in several bladder cancer cell lines. Furthermore, CD46 overexpression triggered phosphorylation of p38 MAPK and protein kinase B (AKT), leading to enhanced activator protein 1 (AP-1) activity via c-Jun upregulation. The inhibition of p38 or AKT pathways attenuated the CD46-induced MMP9 and AP-1 upregulation, indicating that the promotion of MMP9 by CD46 involved activating both p38 MAPK and AKT.Functionally, the upregulation of MMP9 by CD46 translated to increased migratory and invasive capabilities of bladder cancer cells, as well as enhanced in vivo metastasis. Overall, the present study revealed a novel role for CD46 as a metastasis promoter through MMP9 activation in bladder cancers and highlighted the regulatory mechanism of CD46-mediated MMP9 promotion via p38 MAPK and AKT activation.