RB/PLK1-dependent induced pathway by SLAMF3 expression inhibits mitosis and control hepatocarcinoma cell proliferation

// Hicham Bouhlal 1, 2 , Hakim Ouled-Haddou 1, * , Veronique Debuysscher 1, * , Amrathlal Rabbind Singh 1 , Christele Ossart 1, 2 , Aline Reignier 1, 2 , Hakim Hocini 3 , Gregory Fouquet 1 , Mohammed Al Baghami 1, 2 , Melanie Simoes Eugenio 1 , Eric Nguyen-Khac 4 , Jean-Marc Regimbeau 5 , Ingrid Marcq 1 1 Centre Universitaire de Recherche en Sante CURS, CAP-Sante (FED 4231), Universite de Picardie Jules Verne, CHU Sud, Amiens, France 2 Service d’Hematologie Clinique et de Therapie Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France 3 IMRB, Equipe 16, Genomique Medicale, UFR de Medecine, Creteil, France 4 Service Hepato-Gastroenterologie, Centre Hospitalier Universitaire Sud, Amiens, France 5 Service de Chirurgie Digestive Centre Hospitalier Universitaire Sud, Amiens, France * These authors contributed equally to this work Correspondence to: Hicham Bouhlal, e-mail: hicham.bouhlal@u-picardie.fr Amrathlal Rabbind Singh, e-mail: rabbind@gmail.com Ingrid Marcq, e-mail: ingrid.marcq@u-picardie.fr Keywords: SLAMF3, HCC, retinoblastoma factor RB, polo-like kinase 1 (PLK1), mitosis Received: June 18, 2015 Accepted: December 09, 2015 Published: January 20, 2016 ABSTRACT Polo-like kinase PLK1 is a cell cycle protein that plays multiple roles in promoting cell cycle progression. Among the many roles, the most prominent role of PLK1 is to regulate the mitotic spindle formation checkpoint at the M-phase. Recently we reported the expression of SLAMF3 in Hepatocytes and show that it is down regulated in tumor cells of hepatocellular carcinoma (HCC). We also show that the forced high expression level of SLAMF3 in HCC cells controls proliferation by inhibiting the MAPK ERK/JNK and the mTOR pathways. In the present study, we provide evidence that the inhibitory effect of SLAMF3 on HCC proliferation occurs through Retinoblastoma (RB) factor and PLK1-dependent pathway. In addition to the inhibition of MAPK ERK/JNK and the mTOR pathways, expression of SLAMF3 in HCC retains RB factor in its hypophosphorylated active form, which in turn inactivates E2F transcription factor, thereby repressing the expression and activation of PLK1. A clear inverse correlation was also observed between SLAMF3 and PLK expression in patients with HCC. In conclusion, the results presented here suggest that the tumor suppressor potential of SLAMF3 occurs through activation of RB that represses PLK1. We propose that the induction of a high expression level of SLAMF3 in cancerous cells could control cellular mitosis and block tumor progression.