RB/PLK1-dependent induced pathway by SLAMF3 expression inhibits mitosis and control hepatocarcinoma cell proliferation
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Hicham Bouhlal1,2, Hakim Ouled-Haddou1,*, Véronique Debuysscher1,*, Amrathlal Rabbind Singh1, Christèle Ossart1,2, Aline Reignier1,2, Hakim Hocini3, Gregory Fouquet1, Mohammed Al Baghami1,2, Mélanie Simoes Eugenio1, Eric Nguyen-Khac4, Jean-Marc Regimbeau5, Ingrid Marcq1
1Centre Universitaire de Recherche en Santé CURS, CAP-Santé (FED 4231), Université de Picardie Jules Verne, CHU Sud, Amiens, France
2Service d’Hématologie Clinique et de Thérapie Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France
3IMRB, Equipe 16, Génomique Médicale, UFR de Médecine, Créteil, France
4Service Hepato-Gastroenterologie, Centre Hospitalier Universitaire Sud, Amiens, France
5Service de Chirurgie Digestive Centre Hospitalier Universitaire Sud, Amiens, France
*These authors contributed equally to this work
Hicham Bouhlal, e-mail: email@example.com
Amrathlal Rabbind Singh, e-mail: firstname.lastname@example.org
Ingrid Marcq, e-mail: email@example.com
Keywords: SLAMF3, HCC, retinoblastoma factor RB, polo-like kinase 1 (PLK1), mitosis
Received: June 18, 2015 Accepted: December 09, 2015 Published: January 20, 2016
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.
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