Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer.

摘要: Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), show loss major contributing factor increased lung tumorigenesis owing to reduced senescence, not apoptosis, or autophagy. Wnt7a-null mice under de novo conditions both display E-cadherin-to-N-cadherin switch, expression markers senescence-associated secretory phenotype, indicating genetic predisposition these carcinogen-induced tumorigenesis. Interestingly, induced alternate pathway, which was independent β-catenin, distinct from classical oncogene-induced mediated by well-known p16INK4a p19ARF pathways. Mechanistically, via inactivation S-phase kinase-associated protein 2, important regulator Additionally, identified Iloprost, prostacyclin analog, initiates downstream cascades similar Wnt7a, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either its mimic, might represent new class therapeutic treatments cancer.