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.
Highlights
Hepatocellular carcinoma (HCC) is a highly aggressive cancer, which results in more than 600,000 deaths every year worldwide [1]
Inhibition of ERK1/2 and reduction in cell proliferation observed both in Huh-7 and HepG2 confirmed the anti-proliferative effect of SLAMF3 in HCC cells (Supplementary Figure 1A, 1B)
The levels of PLK1 increased during S phase and reached peak at mitosis G2-M and its activity is elevated in tissues and cells having a high mitotic index, that includes cancerous cells [12]
Summary
Hepatocellular carcinoma (HCC) is a highly aggressive cancer, which results in more than 600,000 deaths every year worldwide [1]. The major risk factors of HCC have been identified which includes the infection with hepatitis B or C viruses [2], the balance between cell cycle regulators and cell proliferation is an important determinant of tumor development and/or behavior [3]. The expression of proapoptotic genes is decreased in HCC, the balance between death and survival in HCC is dysregulated due to overactivation of anti-apoptotic pathways. Some growth factors that mediate cell survival are up-regulated in HCC, as well as the molecules involved in the cleavage of www.impactjournals.com/oncotarget their proforms to an active form. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs pathways are reported to be enhanced in HCC cells, conferring on them resistance to apoptotic stimuli [4,5,6,7,8]
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