p27kip1 expression limits H-Ras-driven transformation and tumorigenesis by both canonical and non-canonical mechanisms.

// Ilenia Pellizzari 1,* , Linda Fabris 1,4,* , Stefania Berton 1,* , Ilenia Segatto 1 , Francesca Citron 1 , Sara D’Andrea 1 , Martina Cusan 1 , Sara Benevol 1 , Tiziana Perin 2 , Samuele Massarut 3 , Vincenzo Canzonieri 2 , Monica Schiappacassi 1 , Barbara Belletti 1 and Gustavo Baldassarre 1 1 Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy 2 Pathology Unit, CRO Aviano, National Cancer Institute, Aviano, Italy 3 Breast Surgery Unit, CRO Aviano, National Cancer Institute, Aviano, Italy 4 Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this article Correspondence to: Gustavo Baldassarre, email: // Barbara Belletti, email: // Keywords : p27kip1; stathmin; H-Ras and K-Ras; cell cycle progression; metastasis Received : June 15, 2016 Accepted : July 19, 2016 Published : August 27, 2016 Abstract The tumor suppressor protein p27 Kip1 plays a pivotal role in the control of cell growth and metastasis formation. Several studies pointed to different roles for p27 Kip1 in the control of Ras induced transformation, although no explanation has been provided to elucidate these differences. We recently demonstrated that p27 kip1 regulates H-Ras activity via its interaction with stathmin. Here, using in vitro and in vivo models, we show that p27 kip1 is an important regulator of Ras induced transformation. In H-Ras V12 transformed cells, p27 kip1 suppressed cell proliferation and tumor growth via two distinct mechanisms: 1) inhibition of CDK activity and 2) impairment of MT-destabilizing activity of stathmin. Conversely, in K-Ras4B V12 transformed cells, p27 kip1 acted mainly in a CDK-dependent but stathmin-independent manner. Using human cancer-derived cell lines and primary breast and sarcoma samples, we confirmed in human models what we observed in mice. Overall, we highlight a pathway, conserved from mouse to human, important in the regulation of H-Ras oncogenic activity that could have therapeutic and diagnostic implication in patients that may benefit from anti-H-Ras therapies.