It is well known that the majority of NPC deaths result from tumor metastases rather than from primary tumors. However, the molecular mechanisms underlying the regulation of tumor cell invasion and metastasis of NPC remain incompletely understood. EIF4G1, a member of the translational initiation factor family, is recognized as the central organizing protein in the recruitment of mRNA during translational initiation. Gradually accumulated evidences indicate that increased EIF4G1 expression may play an oncogenic role and promote the process of tumorigenesis. For instance, over-expression of EIF4G1 has been found in inflammatory breast cancer (IBC) and promotes the formation of IBC tumor emboli by enhancing translation of IRES-containing p120 mRNA, which facilitated tumor cell survival . In addition, frequent amplification of EIF4G1 on chromosome 3q27.1 and over-expression of EI4G1 mRNA was also displayed in lung cancer and hypopharyngeal cancer [13, 14], which suggest the involvement of EIF4G1 in tumorigenesis [11, 20]. Yet, it remains largely unknown about the role of EIF4G1 in the pathogenesis of NPC.
In the previous microarray study, we found that the levels of EIF4G1 mRNA in NPC were increased compared to noncancerous nasopharyngeal tissues . In this report, we further presented the proof that EIF4G1 was over-expressed at both mRNA and protein levels in NPC tissues and cell lines. Furthermore, we found that EIF4G1 over-expression was significantly associated with T classification, lymph node involvement, and clinical stages of NPC patients. Our results also indicated that EIF4G1 protein expression was inversely correlated with patients' overall survival time. NPC patients with higher expression levels of EIF4G1 protein had shorter survival time, and the protein levels of EIF4G1 were an independent prognostic factor. These results suggested the clinical significance of EIF4G1 as a biomarker for NPC prognosis.
To understand the biological functions of EIF4G1, we employed the loss-of-function approach, that is, by knocking down the expression level of endogenous EIF4G1. To achieve this purpose, we chose to use NPC 5-8F cells, a cell line with high tumorigenic and metastatic ability. The 5-8F cells exhibit the highest expression levels of endogenous EIF4G1 in all the six NPC cell lines examined, and thus represent an ideal model for our study. Using this system, we identified the roles of EIF4G1 in promoting cell proliferation, cell cycle, migration, and invasion; we further found that EIF4G1 could enhance tumorigenesis in vivo. These results strongly suggest an oncogenic role of EIF4G1 in NPC development.
EIF4G1 may be used as a useful molecular marker for NPC and an indicator for tumor progression and prognosis. In combination with other biomarkers of NPC, EIF4G1 would be useful for novel therapeutic strategies. Assembly of the EIF4E/EIF4G complex plays a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4EBP1, a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (EIF4E), which compete with EIF4G1 for binding to eIF4E and have tumor-suppressor activity. To pharmacologically mimic 4E-BP function Moerke et al developed the most potent small-molecule compound 4EGI-1 for disrupting EIF4E/EIF4G association, which inhibited cap-dependent translation but not initiation factor independent translation. While 4EGI-1 displaces EIF4G from EIF4E, it effectively enhances 4EBP1, a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (EIF-4E), association with EIF4E both in vitro and in cells, and suppressed cell proliferation [22, 23]. Additionally, EIF4G1 has been reported to implicate in another signal pathway. For example, EIF4A/EIF4G complex has been shown to be involved in the key regulation of translation initiation. Tumor suppressor PDCD4[24, 25] could compete with EIF4A for binding to EIF4G1 and thus inhibit the initialization of translation . Although PDCD4 is known to be a key regulator that controls tumor growth and invasion , the role of PDCD4 in NPC progression remains unclear. Recently, in a microarray study, we observed a significant down-expression of PDCD4 in NPC samples . We therefore speculated that EIF4G1 may play a role in NPC by inhibiting the functions of PDCD4. In the present study, we found that the reduction of endogenous EIF4G1 protein expression increased the expression levels of PDCD4. This result supports the potential involvement of EIF4G1 in regulating PDCD4 expression.
In summary, our results provided the first evidence that EIF4G1 may be involved in the development of NPC. In addition, we also demonstrated that EIF4G1 could serve as a biomarker for the prognosis of NPC. Further works are needed to investigate the mechanisms and pathways of NPC pathogenesis mediated by EIF4G1.