Role of p27Kip1 in cell proliferation and motility during oncogenic transformation.

In many human cancers, p27 down-regulation correlates to a worse prognosis suggesting that p27 levels could represent an important determinant in cell transformation and cancer development. Using a mouse model system based on v-src-induced transformation, we show that p27 absence is linked to a more aggressive phenotype, with an increased cell growth and motility. In 3D systems, transformed p27null fibroblasts shift from a mesenchymal spindle-like shape to a more rounded cell morphology, accompanied by amoeboid-like morph-dynamics, membrane ruffling zones and loss of dendritic-like cell extensions. Importantly, the acquirement of an amoeboid motility in p27-/- transformed cells is associated with a higher ability to move in and colonize distant sites, in vivo. The reintroduction of different p27 mutants in transformed p27null cells clearly demonstrates that the control of cell proliferation and motility by p27 represents two distinct functions, both necessary to fully act as a tumor suppressor. In fact, while the N-terminus region is necessary to block cell proliferation, p27 controls cell shape and motility through its C-terminus domain. Interestingly, both the proliferative and motile advantage displayed by v-src-transformed p27-/- cells highlighted also after transformation with the oncogene Ha-Ras, suggesting the existence and the involvement of common pathways responsible for p27 functions. All together, our results demonstrate that p27 expression is an important determinant both in the first steps of cell transformation and tumor establishment as well as in the following progression to tumor dissemination and colonization of distant sites. Moreover, our study demonstrate for the first time that p27 can affect the motile and the invasive behavior by driving and regulating cell plasticity that, in turn, influences tumor cell morphology and movement.