Bouhlal Hicham, Ouled-Haddou Hakim, Debuysscher Véronique, Singh Amrathlal Rabbind, Ossart Christèle, Reignier Aline, Hocini Hakim, Fouquet Gregory, Al Baghami Mohammed, Eugenio Mélanie Simoes, Nguyen-Khac Eric, Regimbeau Jean-Marc, Marcq Ingrid
Centre Universitaire de Recherche en Santé CURS, CAP-Santé (FED 4231), Université de Picardie Jules Verne, CHU Sud, Amiens, France.
Service d'Hématologie Clinique et de Thérapie Cellulaire Centre Hospitalier Universitaire Sud, Amiens, France.
Oncotarget. 2016 Mar 1;7(9):9832-43. doi: 10.18632/oncotarget.6954.
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.
Polo样激酶PLK1是一种细胞周期蛋白，在促进细胞周期进程中发挥多种作用。在众多作用中，PLK1最突出的作用是在M期调节有丝分裂纺锤体形成检查点。最近我们报道了信号淋巴细胞激活分子家族成员3（SLAMF3）在肝细胞中的表达，并表明它在肝细胞癌（HCC）的肿瘤细胞中表达下调。我们还表明，在HCC细胞中强制高表达水平的SLAMF3通过抑制丝裂原活化蛋白激酶（MAPK）细胞外信号调节激酶/应激活化蛋白激酶（ERK/JNK）和哺乳动物雷帕霉素靶蛋白（mTOR）途径来控制增殖。在本研究中，我们提供证据表明，SLAMF3对HCC增殖的抑制作用是通过视网膜母细胞瘤（RB）因子和PLK1依赖性途径发生的。除了抑制MAPK ERK/JNK和mTOR途径外，SLAMF3在HCC中的表达使RB因子保持低磷酸化活性形式，这反过来又使E2F转录因子失活，从而抑制PLK1的表达和激活。在HCC患者中还观察到SLAMF3与PLK表达之间存在明显的负相关。总之，这里呈现的结果表明，SLAMF3的肿瘤抑制潜力是通过激活抑制PLK1的RB发生的。我们提出，在癌细胞中诱导高表达水平的SLAMF3可以控制细胞有丝分裂并阻断肿瘤进展。
