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EIF5A2 (eukaryotic translation initiation factor 5A2) is a conserved acidic protein with a relatively small molecular mass (1.7×104) in the EIF family. The two subtypes of EIF5A in human EIF5A1 have 84% amino acid sequence homology and 94% similarity to EIF5A2, which are encoded by translation initiation factor 51A (TIF 51A) and TIF 51B genes, respectively. However, the biological functions of these two subtypes may vary significantly. EIF5A1 is present in almost all tissues and cells and plays an important role in RNA metabolism and translation elongation. While EIF5A2 is tissue and cell-specific, its mRNA is expressed only in specific tissues (eg, testicular tissue, brain tissue, or part of malignant tumor tissue) and cells.
Characteristic Structure and Biological Function of EIF5A2 Gene
Unlike members of other EIF families, the primary structure of EIF5A2 and EIF5A1 has a polyamine-derived amino acid 8-hydroxy 2,7,10-triaminodecanoic acid. Deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) mediated 8-hydroxy 2,7,10-triaminodecanoic acid modification on lysine 50 residues. This modification plays a crucial role in catalyzing the post-translational modification and activation of EIF5A2. The 8-hydroxy 2,7,10-triaminodecanoic acid modification is a post-translational modification process unique to the EIF5A protein.
Figure 1. Modification and subcellular location of EIF5A2. (Wang, et al. 2015)
After modification with DHS and DOHH, the EIF5A2 protein is converted to a mature active form. Nuclear EIF5A2 complexed with RanGTP and XPO4 mediates the export of mature EIF5A2. However, if acetylation of lysine-47 occurs, EIF5A2 may also accumulate at the nucleus. Li et al. found that EIF5A2 is involved in mRNA-related transcription, translation, and nuclear transport functions, especially in the translation process. EIF5A2 is an upstream regulator of cellular protein synthesis. Any subtle changes in translation initiation factors can lead to large changes in downstream target genes and pathways, resulting in certain biological behavioral changes.
Expression of EIF5A2 in Malignant Tumors
The study found that EIF5A2 is overexpressed in a variety of malignancies(eg nasopharyngeal carcinoma, non-small cell lung cancer, breast cancer, gastric cancer, esophageal squamous cell carcinoma, liver cancer, colorectal cancer, bladder cancer, prostate cancer, cervical cancer, ovarian cancer, malignant melanoma, leukemia, etc.), suggesting that EIF5A2 acts as an oncogene in tumor progression.
The expression of EIF5A2 is closely related to the clinical stage and grade of multiple malignancies. At the same time, EIF5A2 overexpression is closely related to the survival rate of patients with malignant tumors. The 5-year survival rate and disease-free survival rate of EFI5A2 overexpressing patients are low. The expression of EIF5A2 can be used as an independent predictor of poor prognosis in these cancer patients. Moreover, EIF5A2 overexpression is closely related to lymph node metastasis, distant metastasis and vascular metastasis in tumor patients such as esophageal squamous cell carcinoma, liver cancer, colorectal cancer, cervical cancer and malignant melanoma. These findings suggest that EIF5A2 can be used as a prognostic marker for a variety of human tumors.
Huang et al. found that EIF5A2 expression was not significantly associated with age, gender, and clinical stage in patients with nasopharyngeal carcinoma. Yang et al. showed that there was no significant correlation between EIF5A2 expression and gender, age and tumor differentiation in patients with esophageal squamous cell carcinoma, but it was positively correlated with tumor invasion depth. EIF5A2 is an oncogene that undergoes gene amplification in a variety of malignancies. Overexpression of EIF5A2 is closely related to the progression, invasion and postoperative recurrence of malignant tumors. Inhibition of EIF5A2 expression inhibits proliferation of a variety of tumor cells.
Molecular Mechanism of EIF5A2 in Related Tumors
Li et al. found that EIF5A2 is an upstream regulator of the hypoxia-inducible factor-1α (HIF-1α) promoter. EIF5A2 may increase the transcriptional activity of HIF-1α by binding to the HIF-1α promoter region-2000 bp to~1500 bp fragment. EIF5A2 promotes EMT and is positively correlated with the expression of vascular endothelial growth factor (VEGF). In esophageal squamous cell carcinoma, tissue hypoxia leads to the interaction of EIF5A2 with HIF-1α, which in turn leads to up-regulation of EIF5A2 expression and plays an important role in tumor invasion, metastasis and angiogenesis. Tian et al. found that the expression of microRNA (miR)-30b is down-regulated in gastric cancer, and it acts as an inhibitor in tumor cells. miR-30b is located in the 3'-untranslated region (3'-UTR) of EIF5A2 mRNA, suggesting that EIF 5A 2 may be a target gene of miR-30b. And it plays a role in EMT. miR-30b may inhibit the transfer of tumor cells by down-regulating the expression of EIF5A2 and inhibiting EMT.
In liver cancer, EIF5A2 leads to cytoskeletal remodeling by activating Ras homologous oncogenes(Rho) and Ras-associated C3 botulinum toxin substrate 1, Rac1, the Rho/Rac1 pathway and EMT. This plays an important role in the invasion and progression of liver cancer. Fujimura et al. found that EIF5A2 overexpressing pancreatic cancer promotes pancreatic cancer cell proliferation by up-regulating the level of pseudopodium enriched atypical kinase 1 (PEAK1) and the activity of Src family kinase (SFK). The K-Ras/EIF5A2/PEAK1 signaling pathway is critical in the development of pancreatic ductal adenocarcinoma. Deng et al. found that the expression of EIF5A2 was negatively correlated with the expression of miR-203 in colon cancer tissues. EIF5A 2 is a downstream target gene for the direct action of miR-203. miR-203 inhibits proliferation, invasion, and metastasis of colon cancer cells by inhibiting EIF5A2 expression.