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eIF3a is one of the five core proteins involved in the initiation of translation of eIF3. eIF3a is also known as p150, p167, p180, p185, TIF32, EIF3S10, KIAA0139, eIF3-theta and eIF3-p170. Its gene sequence is highly conserved, and the human gene is located in the long sub-region 2 and 6 sub-bands of chromosome 10. eIF3a is involved in the regulation of translation initiation and plays an important role in regulating cell cycle. In addition, protein molecules as a translational stage can significantly affect the expression of other genes and proteins. Regulates the cell cycle and regulates a range of other proteins (such as the cellular regulatory factor p27, tyrosylated alpha-tubulin and nucleoside reductase M2 subunits), which play key roles in regulating cell cycle progression.
Figure 1. A schematic overview of signaling pathways involving eIF3a and their corresponding biological function. (Yin, et al. 2018)
Studies have shown that eIF3a interacts with other subunits of eIF3 (p44, p116), eIF4B, and RNA, so eIF3a was previously thought to play a central role in eIF3 and translation initiation. However, recent studies have found that eIF3-rich subunits and eIF3 lacking this subunit have no significant difference in promoting the formation of pre-initiation complexes during translation initiation. Significant reduction in eIF3a expression by transfection of antisense cDNA only resulted in a 15-20% reduction in overall protein synthesis. These all indicate that eIF3a is not essential for the synthesis of eIF3 and general proteins. These phenomena suggest that eIF3a may not be an essential functional subunit of eIF3, but may play a role in regulating protein synthesis efficiency by combining with other subunits of eIF3 at the beginning of translation.
eIF3a and tumorigenesis
EIF3a expression is elevated in many cancer cells and tissues, such as colon cancer, breast cancer, cervical cancer, stomach cancer, esophageal cancer, lung cancer, oral cancer, and bladder cancer. The elevated expression of eIF3a was first discovered by Bachmann et al. in breast cancer and subsequent studies have confirmed the significant increase in eIF3a expression levels in many cancer cells and tissues. High expression of eIF3a in cancer tissues suggests that eIF3a may be involved in tumor formation to some extent. In the study of the relationship between high expression of eIF3a and tumorigenesis, the expression of eIF3a was significantly decreased in human lung cancer cell line H1299 and breast cancer cell line MCF7, which knocked out eIF3a gene and stably transfected antisense cDNA, and the growth characteristics of cells changed greatly. . At the same time, overexpression of eIF3a increased the proliferation rate of mouse embryonic fibroblast NIH3T3 cells, colony formation, growth independent of support, loss of contact inhibition, high metabolic activity and decreased apoptosis, resulting in malignant transformation of cells. These all indicate that high expression of eIF3a is indispensable in maintaining the malignant phenotype of cells.
eIF3a and Tumor Progression
It is worth mentioning that elevated levels of eIF3a expression usually occur during the early stages of cancer invasiveness. When comparing cervical tissues of different malignant degrees, it was found that the expression of eIF3a was higher in tissues with low intraepithelial neoplasia, while the expression of eIF3a was decreased in highly intraepithelial neoplasia and invasive carcinoma. It is indicated that eIF3a plays a role in the evolution of tumors. It is involved in the early stage of cancer and is involved in the formation of cancer. With the evolution of tumor tissues, high expression of eIF3a may inhibit the progression of tumors.
Most extracellular signals can affect cell proliferation, differentiation, and apoptosis through the RAF-MEK-ERK pathway. Samatar et al. found that continuous activation of the RAF-MEK-ERK signaling pathway often leads to abnormal cell growth and canceration. The study found that eIF3a binds to the SHC and Raf1 proteins in the extracellular signal-regulated kinase pathway and, by binding to Raf1, isolates Raf1 from the EGF-activated ERK signaling pathway. The RAF-MEK-ERK signaling pathway is then inhibited and becomes an important blocker of the RAF-MEK-ERK signaling pathway. Therefore, down-regulation of eIF3a enhances ERK activation and prolongs activation time.
eIF3a and Chemosensitivity
The role of eIF3a in the evolution of tumors is volatility. The study found that high expression of eIF3a is a favorable factor for tumor cells that are interfered with by chemotherapy drugs. Patients with high expression of eIF3a in cervical, esophageal, oral, and lung cancer have increased sensitivity to chemotherapy-induced chemotherapy, and have a better prognosis and overall survival after receiving platinum-based chemotherapy. It is well known that DNA repair abnormalities are an important mechanism of tumor resistance. The study found that down-regulation of eIF3a expression resulted in increased expression of DNA base excision repair proteins at the translational level rather than at the transcriptional level, and increased DNA repair capacity, thereby conferring resistance to chemotherapy drugs that are mediated by DNA damage. After that, Yin et al. used bioinformatics to analyze the 5, UTR sequence of the DNA base excision repair protein RPA2 mRNA regulated by eIF3a, and construct different luciferase reporter plasmids for detecting promoter and IRES activity. After in vitro transcription and purification, H1299 cells were transfected and their luciferase activity was measured. It was found that RPA2 5, UTR has an IRES element located at -50~-150 bp upstream of the translation initiation site. It was also confirmed that eIF3a inhibits the translation of PRA2 by directly binding to the IRES, thereby attenuating DNA repair ability and improving the sensitivity of tumor patients to chemotherapy drugs with DNA damage as a mechanism.
In addition, the eIF3a gene polymorphism also affects patients' sensitivity to platinum-based chemotherapy. Xu et al found that patients with lung cancer with eIF3a rs3740556 mutation had a better response to platinum-based chemotherapy (P<0.05) and had longer survival time. Patients with eIF3a rs3740556 A allele have a better prognosis after platinum chemotherapy. Therefore, eIF3a can be used as a tool to predict the drug resistance of platinum chemotherapy in patients with lung cancer.