Wnt signaling potentiates nevogenesis

摘要

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human neèi are a paradigm for tumor-suppressièe senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescenceassociated proliferation arrest in suppression of transformation. Preèious studies showed that actièation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present eèidence that repression of Wnt signaling contributes to melanocyte senescence in èitro. Surprisingly, Wnt signaling is actièe in many senescent human melanocytes in neèi, and this is linked to histological indicators of higher proliferatièe andmalignant potential. In a mouse, actièated Wnt signaling delays senescenceassociated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate neèogenesis in èièo by delaying senescence. Further, we suggest that actièated Wnt signaling in human neèi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.