Gene Summary

Gene:EIF3E; eukaryotic translation initiation factor 3 subunit E
Aliases: INT6, EIF3S6, EIF3-P48, eIF3-p46
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:eukaryotic translation initiation factor 3 subunit E
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EIF3E (cancer-related)

Hu J, Luo H, Xu Y, et al.
The Prognostic Significance of
Cancer Invest. 2019; 37(4-5):199-208 [PubMed] Related Publications
Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear.

Cuesta R, Berman AY, Alayev A, Holz MK
Estrogen receptor α promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f).
J Biol Chem. 2019; 294(7):2267-2278 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Approximately two thirds of all breast cancer cases are estrogen receptor (ER)-positive. The treatment of this breast cancer subtype with endocrine therapies is effective in the adjuvant and recurrent settings. However, their effectiveness is compromised by the emergence of intrinsic or acquired resistance. Thus, identification of new molecular targets can significantly contribute to the development of novel therapeutic strategies. In recent years, many studies have implicated aberrant levels of translation initiation factors in cancer etiology and provided evidence that identifies these factors as promising therapeutic targets. Accordingly, we observed reduced levels of the eIF3 subunit eIF3f in ER-positive breast cancer cells compared with ER-negative cells, and determined that low eIF3f levels are required for proper proliferation and survival of ER-positive MCF7 cells. The expression of eIF3f is tightly controlled by ERα at the transcriptional (genomic pathway) and translational (nongenomic pathway) level. Specifically, estrogen-bound ERα represses transcription of the

Wang L, Ouyang L
Effects of EIF3B gene downregulation on apoptosis and proliferation of human ovarian cancer SKOV3 and HO-8910 cells.
Biomed Pharmacother. 2019; 109:831-837 [PubMed] Related Publications
In order to investigate the role of EIF3B (eukaryotic translation initiation factor 3B, EIF3B) gene in the proliferation and apoptosis of ovarian cancer cells, a lentiviral vector system and shEIF3B lentiviral vector were constructed to transfect human ovarian cancer cells. SKOV3 and HO-8910 cells were used in this experiment. The cell growth was detected by Celigo cell counting assay, the apoptosis rate was measured by flow cytometry and the cell proliferation ability of lentivirus transfected cells was tested by MTT assay and clone formation assay. Results showed that the specific shRNA had a significant inhibitory effect on the expression of EIF3B gene. Compared with the negative control, the expression of EIF3B mRNA and protein in SKOV3 and HO-8910 cells were significantly inhibited in the knockdown group. Then the proliferation rate of each group was tested, we found that SKOV3 and HO-8910 cells in siRNA lentivirus infected group was significantly decreased. Same result was obtained from the clonogenic assay of which the colony formation of transfected cells was significantly inhibited compared with the control group. Further study showed that the proliferation inhibitory effect was associated with as increased apoptosis rate of SKOV3 and HO-8910 cells in EIF3B knockdown groups. All in all, inhibition of EIF3B gene expression significantly inhibit the proliferation of ovarian cancer cells and increase the apoptosis of ovarian cancer cells. These results provide a new basis for the study of the molecular mechanism of ovarian cancer development and provide new target gene for ovarian cancer treatment.

Li G, Wang K, Li Y, et al.
Role of eIF3a in 4-amino-2-trifluoromethyl-phenyl retinate-induced cell differentiation in human chronic myeloid leukemia K562 cells.
Gene. 2019; 683:195-209 [PubMed] Related Publications
4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been demonstrated its anti-tumor effect through inducing differentiation and inhibiting proliferation. Eukaryotic initiation factor 3a (eIF3a) plays a critical role in affecting tumor cell proliferation and differentiation. However, whether eIF3a is implicated in chronic myeloid leukemia cells differentiation remains unclear. Our results demonstrated that eIF3a could be suppressed by ATPR in K562 cells. The results also confirmed that ATPR could arrest cell cycle in G0/G1 phase and induced differentiation. Moreover, over-expression of eIF3a promoted not only protein expression of c-myc and cyclin D1, but also prevented the expression of p-Raf-1, p-ERK and the myeloid differentiation markers CD11b and CD14 and had an influence on inducing the morphologic mature. However, silencing eIF3a expression by small interfering RNA could have an adverse effect on K562 cells. In addition, PD98059 (a MEK inhibitor) could block cell differentiation of CML cells and contributed to the expression of c-myc and cyclin D1. In conclusion, these results indicated that eIF3a played an important role in ATPR-induced cell differentiation in K562 cells, its mechanism might be related to its ability in regulating the activation of ERK1/2 signaling pathway in vitro.

Wee Y, Wang T, Liu Y, et al.
A pan-cancer study of copy number gain and up-regulation in human oncogenes.
Life Sci. 2018; 211:206-214 [PubMed] Related Publications
AIM: There has been limited research on CNVs in oncogenes and we conducted a systematic pan-cancer analysis of CNVs and their gene expression changes. The aim of the present study was to provide an insight into the relationships between gene expression and oncogenesis.
MAIN METHODS: We collected all the oncogenes from ONGene database and overlapped with CNVs TCGA tumour samples from Catalogue of Somatic Mutations in Cancer database. We further conducted an integrative analysis of CNV with gene expression using the data from the matched TCGA tumour samples.
KEY FINDINGS: From our analysis, we found 637 oncogenes associated with CNVs in 5900 tumour samples. There were 204 oncogenes with frequent copy number of gain (CNG). These 204 oncogenes were enriched in cancer-related pathways including the MAPK cascade and Ras GTPases signalling pathways. By using corresponding tumour samples data to perform integrative analyses of CNVs and gene expression changes, we identified 95 oncogenes with consistent CNG occurrence and up-regulation in the tumour samples, which may represent the recurrent driving force for oncogenesis. Surprisingly, eight oncogenes shown concordant CNG and gene up-regulation in at least 250 tumour samples: INTS8 (355), ECT2 (326), LSM1 (310), DDHD2 (298), COPS5 (286), EIF3E (281), TPD52 (258) and ERBB2 (254).
SIGNIFICANCE: As the first report about abundant CNGs on oncogene and concordant change of gene expression, our results may be valuable for the design of CNV-based cancer diagnostic strategy.

Choe J, Lin S, Zhang W, et al.
mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.
Nature. 2018; 561(7724):556-560 [PubMed] Article available free on PMC after 15/02/2020 Related Publications

Tian Y, Zhao K, Yuan L, et al.
EIF3B correlates with advanced disease stages and poor prognosis, and it promotes proliferation and inhibits apoptosis in non-small cell lung cancer.
Cancer Biomark. 2018; 23(2):291-300 [PubMed] Related Publications
BACKGROUND: Although up-regulation of EIF3B correlates with poor prognosis in carcinomas, the role of EIF3B in non-small cell lung cancer (NSCLC) is rarely known.
OBJECTIVE: We aimed to investigate correlation of EIF3B with clinicopathological features and prognosis in NSCLC patients, and clarify its effect on cells proliferation and apoptosis.
METHODS: Two hundred and eleven NSCLC patients underwent surgery were retrospectively reviewed. Tumor tissue and paired adjacent tissue were obtained. EIF3B expression was detected by immunohistochemistry, qPCR and western blot. EIF3B inhibitor, blank inhibitor, blank mimic and EIF3B mimic plasmids were transfected to A-549 cells. Cells proliferation and apoptosis were measured by CCK-8 and AV/PI. All processes were repeated for validation in PC9 cells.
RESULTS: EIF3B expression increased in tumor tissue compared to paired adjacent tissue, and positively correlated with tumor size, lymph node metastasis and TNM stage. K-M curves revealed patients with EIF3B high expression had shorter DFS and OS, and its high expression independently predicted unfavorable DFS and OS. In vitro, EIF3B expression increased in NSCLC cells compared to normal cells. EIF3B increased cells proliferation but inhibited cells apoptosis.
CONCLUSIONS: EIF3B overexpression correlates with advanced disease conditions and poor prognosis, and it promotes cells proliferation while inhibits apoptosis in NSCLC.

Wang X, Wang H, Zhao S, et al.
Eukaryotic translation initiation factor EIF3H potentiates gastric carcinoma cell proliferation.
Tissue Cell. 2018; 53:23-29 [PubMed] Related Publications
Eukaryotic translation initiation factor 3 subunit H (EIF3H) is required for the progression of several types of cancer. However, little is known about the function of EIF3H in gastric carcinoma. To address this issue, in the present study, we investigated EIF3H genetic alterations in and expression of EIF3H in gastric cancer tissue samples using cBioPortal and Oncomine databases. Endogenous EIF3H expression was knocked down in MGC80-3 and AGS gastric cancer cell lines by lentivirus-mediated RNA interference. We confirmed the knockdown efficiency by quantitative real-time PCR and western blotting and evaluated the effects of EIF3H silencing on cell proliferation of gastric cancer with the cell viability and colony formation assays and by flow cytometry. The OncoPrint of EIF3H generated using cBioPortal indicated that EIF3H genetic alterations (mutation, deletion and amplification) were present in two gastric cancer sample sets. The Oncomine analysis revealed that EIF3H mRNA level was upregulated in gastric cancer tissues. EIF3H knockdown inhibited cell proliferation and colony formation in gastric cancer lines and led to cell cycle arrest at the G0/G1 phase, while inducing apoptosis via up- and downregulation of pro- and anti-apoptotic factors, respectively. These results indicate that EIF3H can serve as a novel therapeutic target for the clinical treatment of gastric cancer.

Yu G, Liao J, Wu J, et al.
The proliferation of colorectal cancer cells is suppressed by silencing of EIF3H.
Biosci Biotechnol Biochem. 2018; 82(10):1694-1701 [PubMed] Related Publications
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Eukaryotic translation initiation factor 3, subunit H (EIF3H) is a subunit of EIF3, which is involved in mRNA recruitment and ribosomal complex disassembly and is known to be a driver of cell proliferation and survival in cancer. To investigate its function in colorectal cancer, the Oncomine database was used to evaluate the expression of EIF3H in human colorectal cancer and normal tissues. Then, we constructed a Lentivirus shorthair EIF3H vector (Lv-shEIF3H) to silence EIF3H expression in the colorectal cancer cell lines HCT116 and SW1116. We observed impaired cell growth and colony formation in these silenced cell lines. In addition, we showed that EIF3H knock-down led to cell apoptosis. In conclusion, EIF3H plays key roles in the apoptosis in colorectal cancer cells, which suggests EIF3H as a potential diagnostic biomarker in colorectal cancer.

Yin Y, Long J, Sun Y, et al.
The function and clinical significance of eIF3 in cancer.
Gene. 2018; 673:130-133 [PubMed] Related Publications
Abnormal regulation of gene expression is essential for tumorigenesis. Several studies indicate that regulation of oncogene expression and neoplastic transformation are controlled by subunits of eukaryotic translation initiation factors (eIFs). Eukaryotic translation initiation factor 3 (eIF3) is the largest (800 kDa) and the most complex mammalian initiation factor. It is composed of 13 non-identical polypeptides designated as eIF3a-m and plays a pivotal role in protein synthesis that bridges the 43S pre-initiation complex and eIF4F-bound mRNA. However, the functional roles of individual subunits are not yet very clear. This review presents on several of aberrant expressed eIF3 subunits which are detected in various human cancers and the associated mechanisms have been acknowledged or are still not sure. Finally, identifying novel targets and biomarkers for caner is of great importance in early diagnosis and treatment of cancer. eIF3 may be a novel target molecule in drug development for cancer treatment and prevention.

Gomes-Duarte A, Lacerda R, Menezes J, Romão L
eIF3: a factor for human health and disease.
RNA Biol. 2018; 15(1):26-34 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
The eukaryotic initiation factor 3 (eIF3) is one of the most complex translation initiation factors in mammalian cells, consisting of several subunits (eIF3a to eIF3m). It is crucial in translation initiation and termination, and in ribosomal recycling. Accordingly, deregulated eIF3 expression is associated with different pathological conditions, including cancer. In this manuscript, we discuss the interactome and function of each subunit of the human eIF3 complex. Furthermore, we review how altered levels of eIF3 subunits correlate with neurodegenerative disorders and cancer onset and development; in addition, we evaluate how such misregulation may also trigger infection cascades. A deep understanding of the molecular mechanisms underlying eIF3 role in human disease is essential to develop new eIF3-targeted therapeutic approaches and thus, overcome such conditions.

Zhu T, Gao Y, Li L, et al.
Aberration in translation initiation and associated diseases: Role of the eukaryotic translation initiation factor 3A.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017; 42(10):1204-1211 [PubMed] Related Publications
Translation control in eukaryotes contributes significantly to gene expression regulation during cellular processes, which enables rapid changes of specific proteins to maintain cellular homeostasis. Eukaryotic translation is a multiple-step process that comprised of four phases: initiation, elongation, termination and ribosome recycling. The initiation phase is rate-limiting and orchestrated by a set of eukaryotic translation initiation factors (eIFs). Defects in translation initiation can result in a series of diseases. Among all eIFs, eIF3 is the largest and less-known initiation factor due to its intrinsic complexity. Aberration in eIF3A, the largest subunit of eIF3, is known to contribute to carcinogenesis and protection against evolution into higher-grade malignancy, and the altered expression or mutation of eIF3A affects the responses of cancer patients to platinum-based chemotherapy. Besides its role in cancinogenesis, eIF3A is also implicated in fibrosis, and the agents inhibiting eIF3A delay the progression of this disorder. The dual roles of eIF3A in tumorigenesis are probably due to the regulation of translation of different mRNAs at different stages of tumor progression by eIF3A. In turn the encoded products serve as pro-tumor or anti-tumor proteins at different stages.

Zhao W, Li X, Wang J, et al.
Decreasing Eukaryotic Initiation Factor 3C (EIF3C) Suppresses Proliferation and Stimulates Apoptosis in Breast Cancer Cell Lines Through Mammalian Target of Rapamycin (mTOR) Pathway.
Med Sci Monit. 2017; 23:4182-4191 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
BACKGROUND Translation initiation is the rate limiting step of protein synthesis and is highly regulated. Eukaryotic initiation factor 3C (EIF3C), an oncogene overexpressed in several human cancers, plays an important role in tumorigenesis and cell proliferation. MATERIAL AND METHODS Immunohistochemistry was used to determine the expression of EIF3C in breast cancer tissues from 42 patients. We investigated whether EIF3C silencing decreases breast cancer cell proliferation as assessed by colony formation assay, and whether EIF3C gene knockdown induces apoptosis as assessed by flow cytometry analysis. We utilized the stress and apoptosis signaling antibody array kit, while p-ERK1/2, p-Akt, p-Smad2, p-p38 MAPK, cleaved caspase-3, and cleaved caspase-7 were explored between EIF3C-siRNA and controls. Furthermore, the effects of EIF3C gene knockdown in mTOR pathway were analyzed by western blotting for different cell lines. RESULTS In EIF3C-positive tumors, 32 out of 42 showed significantly higher frequencies of high grade group by immunoreactivity (p=0.0016). BrdU incorporation after four days of cell plating was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls, with average changes of 7.8-fold (p<0.01). Clone number was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls (p<0.05). Cell apoptosis was significantly increased in the EIF3C-siRNA group when compared with the cells that were transfected with scrambled siRNA (3.51±0.0842 versus 13.24±0.2307, p<0.01). The mTOR signaling pathway was involved in decreasing EIF3C translational efficiency. CONCLUSIONS Unveiling the mechanisms of EIF3 action in tumorigenesis may help identify attractive targets for cancer therapy.

Liu GZ, Liu JZ, Li XQ, et al.
Knockdown of eukaryotic translation initiation factor 3 subunit D (eIF3D) inhibits proliferation of acute myeloid leukemia cells.
Mol Cell Biochem. 2018; 438(1-2):191-198 [PubMed] Related Publications
Various eukaryotic translation initiation factors (eIFs) have been implicated in carcinoma development. Eukaryotic translation initiation factor 3 subunit D (eIF3D) has recently been shown to regulate the growth of several types of human cancer cells. However, the function of eIF3D in acute myeloid leukemia (AML) remains unclear. In this study, we investigated the expression of eIF3D in three AML cell lines and a lymphoblast cell line, and found that eIF3D was expressed in all four leukemia cell lines. To explore the role of eIF3D in AML cell proliferation, lentivirus-mediated RNA interference was applied to knock down the expression of eIF3D in U937 cells. The expression of eIF3D was significantly downregulated in U937 cells after eIF3D knockdown, as confirmed by quantitative real-time PCR (qRT-PCR) and Western blot analysis. Knockdown of eIF3D significantly inhibited proliferation of U937 cells. Furthermore, flow cytometry analysis revealed that eIF3D silencing induced cell cycle arrest at the G2/M phase, ultimately leading to apoptosis. Our results indicate that eIF3D plays a key role in the proliferation of AML cells, and suggest that eIF3D silencing might be a potential therapeutic strategy for leukemia.

Han T, Schatoff EM, Murphy C, et al.
R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine.
Nat Commun. 2017; 8:15945 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.

Ali J, Sabiha B, Jan HU, et al.
Genetic etiology of oral cancer.
Oral Oncol. 2017; 70:23-28 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. It accounts for 2.5% of all new cancer cases and 1.9% of all cancer deaths annually. More than 90% of oral cancers (occurring in the mouth, lip, and tongue) are oral squamous cell carcinoma. The incidence rate of oral cancer varies widely throughout the world, with an evident prevalence in South Asian countries. This high incidence occurs in correlation with oral cancer-associated behaviors such as alcohol, tobacco use. Researchers have reported that these behaviors lead to genetic variations in tumor suppressor genes (APC, p53), proto-oncogenes (Myc), oncogene (Ras) and genes controlling normal cellular processes (EIF3E, GSTM1). Processes such as segregation of chromosomes, genomic copy number, loss of heterozygosity, telomere stabilities, regulations of cell-cycle checkpoints, DNA damage repairs and defects in notch signaling pathways are involved in causing oral cancer. In order to develop preventive and therapeutic options, it is necessary to comprehend the basic molecular mechanisms forcing oral tumorigenesis. This review examines, in detail, the mechanisms of genetic alteration which are considered to be responsible for the initiation of oral cancer.

Xu JZ, Wen F, Wang XR
The eIF3a Arg803Lys genetic polymorphism is associated with susceptibility to and chemoradiotherapy efficacy in cervical carcinoma.
Kaohsiung J Med Sci. 2017; 33(4):187-194 [PubMed] Related Publications
We aimed to explore the correlations between eukaryotic translation initiation factor 3, subunit A (eIF3a) polymorphisms and susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. Between August 2007 and August 2011, 176 patients with cervical carcinoma were enrolled as the case group, and 180 healthy individuals were selected as the control group. eIF3a Arg803Lys C>T genotypes were detected by hemi-nested polymerase chain reaction restriction fragment length polymorphism. All patients received chemoradiotherapy and were evaluated for efficacy. Compared with carriers of the CC genotype, carriers of the T genotype of the eIF3a Arg803Lys C>T polymorphism had a higher risk of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism was associated with tumor size, differentiation degree, Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). The overall response rate of the case group was 69.32% (122/176). The response rate of CC genotype carriers was higher compared to patients with the CT+TT genotypes. Binary-logistic regression analysis showed that tumor size, FIGO stage, LNM, and the eIF3a Arg803Lys C>T polymorphism were influencing factors for chemoradiotherapy efficacy. Univariate analysis revealed that age, eIF3a Arg803Lys C>T polymorphism, differentiation degree, FIGO stage, and LNM were prognostic factors of cervical carcinoma, and multivariate analysis showed that age ≥ 60 years, higher FIGO stage, and LNM, as well as the CT and TT genotypes of the eIF3a Arg803Lys C>T polymorphism, were risk factors related to the prognosis of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism is connected with a higher susceptibility to cervical carcinoma and may affect chemoradiotherapy efficacy in and prognosis of cervical carcinoma.

Li T, Li S, Chen D, et al.
Transcriptomic analyses of RNA-binding proteins reveal eIF3c promotes cell proliferation in hepatocellular carcinoma.
Cancer Sci. 2017; 108(5):877-885 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
RNA-binding proteins (RBPs) play fundamental roles in the RNA life cycle. The aberrant expression of RBPs is often observed in human disease, including cancer. In this study, we screened for the expression levels of 1542 human RBPs in The Cancer Genome Atlas liver hepatocellular carcinoma samples and found 92 consistently upregulated RBP genes in HCC compared with normal samples. Additionally, we undertook a Kaplan-Meier analysis and found that high expression of 15 RBP genes was associated with poor prognosis in patients with HCC. Furthermore, we found that eIF3c promotes HCC cell proliferation in vitro as well as tumorigenicity in vivo. Gene Set Enrichment Analysis showed that high eIF3c expression is positively associated with KRAS, vascular endothelial growth factor, and Hedgehog signaling pathways, all of which are closely associated with specific cancer-related gene sets. Our study provides the basis for further investigation of the molecular mechanism by which eIF3c promotes the development and progression of HCC.

Zhang Y, Wang P, Zhang Q, et al.
eIF3i activity is critical for endothelial cells in tumor induced angiogenesis through regulating VEGFR and ERK translation.
Oncotarget. 2017; 8(12):19968-19979 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Translational control is a critical step in the regulation of gene expression. Accumulating evidence shows that translational control of a subgroup of mRNAs tends to be selective. However, our understanding of the function of selective translational control in endothelial cells is still incomplete. We found that a key translational regulator, eIF3i, is highly expressed in endothelial cells during embryonic and tumor angiogenesis. Knockdown of eIF3i restrained cell proliferation and migration in endothelial cells. In zebrafish angiogenesis model, eIF3i mutant endothelial cells could not respond to induction signals from tumor mass. Mechanistically, we showed that eIF3i knockdown reduced VEGFR/ERK signaling by down-regulating VEGFR2 and ERK protein expression. Gene therapy model suggested that the growth and metastasis of cancer cells were suppressed by eIF3i shRNA. Therefore, our work established a selective translational regulatory mechanism during tumor induced angiogenesis and suggested that targeting eIF3i may be applicable for anticancer therapy.

Fang C, Chen YX, Wu NY, et al.
MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway.
Sci Rep. 2017; 7:40384 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual-luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3'UTR of eIF3a. In addition, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells.

Luo S, Zhao J, Fowdur M, et al.
Highly expressed ribosomal protein L34 indicates poor prognosis in osteosarcoma and its knockdown suppresses osteosarcoma proliferation probably through translational control.
Sci Rep. 2016; 6:37690 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
Osteosarcoma has devastating health implications on children and adolescents. However, due to its low incidence and high tumor heterogeneity, it is hard to achieve any further improvements in therapy and overall survival. Ribosomal protein L34 (RPL34) has been increasingly recognized to promote the proliferation of malignant cells, but its role in osteosarcoma has not been investigated. In this study, real-time quantitative PCR (RT-qPCR) and immunohistochemistry revealed that RPL34 was highly expressed in osteosarcoma tissues when compared to adjacent tissues and normal bone tissues. Survival analysis showed that high expression of RPL34 predicted a poor prognosis for osteosarcoma patients. Knockdown of RPL34 in Saos-2 cells via lentivirus-mediated small interfering RNA (siRNA) significantly inhibited cell proliferation, induced cell apoptosis and G2/M phase arrest. Moreover, screening of transcription factors using University of California Santa Cruz (UCSC) Genome Browser, protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and pathway enrichment analysis revealed that MYC participates in the transcriptional regulation of RPL34, which interacts with the subunits of eukaryotic translation initiation factor 3 (eIF3) and probably involves the translational control of growth-promoting proteins. Our findings suggest that RPL34 plays an important role in the proliferation of osteosarcoma cells.

Senfter D, Madlener S, Krupitza G, Mader RM
The microRNA-200 family: still much to discover.
Biomol Concepts. 2016; 7(5-6):311-319 [PubMed] Related Publications
In the last decade, microRNAs (miRs or miRNAs) became of great interest in cancer research due to their multifunctional and active regulation in a variety of vital cellular processes. In this review, we discuss the miR-200 family, which is composed of five members (miR-141, miR-200a/200b/200c and miR-429). Although being among the best investigated miRNAs in the field, there are still many open issues. Here, we describe the potential role of miR-200 as prognostic and/or predictive biomarker, its influence on motility and cell migration as well as its role in epithelial to mesenchymal transition (EMT) and metastasis formation in different tumour types. Recent studies also demonstrated the influence of miR-200 on drug resistance and described a correlation between miR-200 expression levels and overall survival of patients. Despite intense research in this field, the full role of the miR-200 family in cancer progression and metastasis is not completely understood and seems to differ between different tumour types and different cellular backgrounds. To elucidate these differences further, a finer characterisation of the role of the individual miRNA-200 family members is currently under investigation.

Yin JY, Dong Z, Zhang JT
eIF3 Regulation of Protein Synthesis, Tumorigenesis, and Therapeutic Response.
Methods Mol Biol. 2017; 1507:113-127 [PubMed] Related Publications
Translation initiation is the rate-limiting step of protein synthesis and highly regulated. Eukaryotic initiation factor 3 (eIF3) is the largest and most complex initiation factor consisting of 13 putative subunits. A growing number of studies suggest that eIF3 and its subunits may represent a new group of proto-oncogenes and associates with prognosis. They regulate translation of a subset of mRNAs involved in many cellular processes including proliferation, apoptosis, DNA repair, and cell cycle. Therefore, unveiling the mechanisms of eIF3 action in tumorigenesis may help identify attractive targets for cancer therapy. Here, we describe a series of methods used in the study of eIF3 function in regulating protein synthesis, tumorigenesis, and cellular response to therapeutic treatments.

Sesen J, Casaos J, Scotland SJ, et al.
The Bad, the Good and eIF3e/INT6.
Front Biosci (Landmark Ed). 2017; 22:1-20 [PubMed] Related Publications
Recent research on translation and protein synthesis in several pathologies, including cancer, peripheral artery disease, and wound healing, demonstrates the key role played by translational factors in tumorigenic and angiogenic processes. This review will focus on one specific translational factor, eIF3e also called INT6, the "e" subunit of the translation initiation factor eIF3. INT6/eIF3e has recently been described as a multifunction protein playing a role in translation, protein degradation, DNA repair, nonsense-mediated mRNA decay, cell cycle and control of cell response to low oxygen (hypoxia or ischemia) through modulation of the Hypoxia Inducible Factors (HIFs). Interestingly, INT6/eIF3e is a double-edged sword that has both oncogenic and tumor suppressive abilities. In addition to its role in tumorigenesis, its silencing has recently been suggested as a potential therapeutic strategy to improve cell survival and function after ischemic injuries. Although a deeper understanding of the molecular mechanisms involved in these pathophysiological functions is essential, particularly to transform the

Wang M, Xiao X, Zeng F, et al.
Common and differentially expressed long noncoding RNAs for the characterization of high and low grade bladder cancer.
Gene. 2016; 592(1):78-85 [PubMed] Related Publications
Our study aimed to explore long non-coding RNAs (lncRNAs) contributing to the development of bladder cancer, as well as to identify more critical DEGs and lncRNAs that would characterize low- and high-grade bladder cancer. The microarray data of GSE55433 was downloaded from Gene Expression Omnibus database, including 57 urothelial cancer samples (23 low-grade NMI, 14 high-grade NMI and 20 invasive tumors) and 26 normal controls. The differentially expressed genes (DEGs) and differentially expressed lncRNAs were identified in 3 groups (low-grade NMI vs. normal, high-grade NMI vs. normal and invasive UC vs. normal). Functional enrichment analysis was performed upon the DEGs in different groups. Besides, protein-protein interaction (PPI) network was constructed based on common DEGs and remaining DEGs in each group. Co-expression analysis was performed to identify the co-expressed DEG-lncRNAs pairs. Different number of DEGs and differentially expressed lncRNAs were respectively identified from those 3 groups. NONHSAG013805 (down-regulated) and NONHSAG009271 (down-regulated) were common lncRNAs. NONHSAG013805 was connected with the down-regulated gene EIF3E and NONHSAG009271 was linked to MYL12A (down-regulated). Moreover, NONHSAG034203 (up-regulated) was co-expressed with ADM5 (up-regulated) in low-grade NMI cancer, while the down-regulated NONHSAG045391 was connected with the down-regulated DEGs DAD1 and STUB1 in high-grade NMI cancer and invasive bladder cancer. Our study indicates that NONHSAG013805 and NONHSAG009271 may play key roles in bladder cancer via co-expressing with EIF3E and MYL12A, respectively. Moreover, NONHSAG034203 may be involved in low-grade NMI bladder cancer via targeting ADM5, while NONHSAG045391 may contribute to high-grade NMI and invasive bladder cancer via targeting DAD1 and STUB1.

Zhu Q, Qiao GL, Zeng XC, et al.
Elevated expression of eukaryotic translation initiation factor 3H is associated with proliferation, invasion and tumorigenicity in human hepatocellular carcinoma.
Oncotarget. 2016; 7(31):49888-49901 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
AIM: We studied the role of eukaryotic translation initiation factor 3 subunit H (EIF3H) in hepatocellular carcinoma (HCC) progression.
RESULTS: High EIF3H expression was observed in 50.23% patients. Upregulation of EIF3H is an independent predictor for greater rates of cancer recurrence and shorter overall survival in HCC patients. Knockdown of EIF3H expression in HCC cells promoted apoptosis, and inhibited cell growth, colony formation, migration, as well as xenograft growth. TGF-βand MAPK pathways are potentially targeted by EIF3H.
METHODS: EIF3H mRNA expression was measured in HCC tissue samples and paired non-tumor samples (N=60) and results were validated in another dataset of 215 HCC patients. Then EIF3H expression and clinical outcomes were correlated. Malignant phenotypes were studied after EIF3H expression was knocked down with siRNA in HCC cell lines. EIF3H targeted pathways were identified by microarray analysis.
CONCLUSION: EIF3H is frequently upregulated and is an independent prognostic marker for HCC patients and EIF3H inhibition mitigates the malignant phenotype. Our data provide novel insight into the function of EIF3H in HCC progression, and suggest that EIF3H may be a potentially valuable biomarker for HCC.

Liu K, Lei Z, Yao H, et al.
Impact of a Eukaryotic Translation Initiation Factor 3a Polymorphism on Susceptibility to Gastric Cancer.
Med Princ Pract. 2016; 25(5):461-5 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
OBJECTIVE: To investigate single nucleotide polymorphisms in the eukaryotic translation initiation factor 3a (eIF3a) gene and the risk for gastric cancer within the Chinese population.
SUBJECTS AND METHODS: A total of 322 patients with gastric cancer were selected as the patient group and 340 non-gastric cancer patients were selected as the control group using the case-control method. Polymerase chain reaction-sequence-specific primer technology was leveraged to genotype the rs77382849 single nucleotide polymorphism in the eIF3a gene. The demographic characteristics of the study population and other exposures to risk factors were collected. Unconditional logistic regression analysis was performed to determine the association between the risk factors and gastric cancer.
RESULTS: A higher frequency of the eIF3a rs77382849 GG homozygote genotype was observed in the gastric cancer patients compared with the controls (63.98 vs. 54.41%, p < 0.05). After adjustment of exposure risks, such as age, gender, smoking, and drinking, the rs77382849 single nucleotide polymorphism was still associated with susceptibility to gastric cancer. When the eIF3a rs77382849 GG homozygote genotype was used as the reference group, the GA genotype (GA vs. GG: OR = 0.545, 95% CI: 0.386-0.769, p = 0.001) and AA genotype (AA vs. GG: OR = 0.245, 95% CI: 0.072-0.836, p = 0.025) were both correlated with a significantly decreased risk for gastric cancer development.
CONCLUSION: An association between eIF3a rs77382849 polymorphism and susceptibility to gastric cancer was observed in these Chinese patients.

Kozel C, Thompson B, Hustak S, et al.
Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.
Nucleic Acids Res. 2016; 44(18):8704-8713 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.

Xu F, Xu CZ, Gu J, et al.
Eukaryotic translation initiation factor 3B accelerates the progression of esophageal squamous cell carcinoma by activating β-catenin signaling pathway.
Oncotarget. 2016; 7(28):43401-43411 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors. Eukaryotic translation initiation factors 3B (EIF3B) is considered to influence tumor proliferation, invasion, apoptosis and cell cycle, which act together to promote the progression of tumors. However, the role of EIF3B in ESCC is unknown. This study aims to explore the clinical and biological role of EIF3B in ESCC.
RESULTS: EIF3B expressions were up-regulated in both ESCC tissues and cell lines. Overexpression of EIF3B was associated with tumor depth, lymph node metastasis and advanced TNM stage. Importantly, patients with high EIF3B expression suffered shorter overall and disease-free survival. Knockdown of EIF3B could inhibit cell proliferation and invasion, promote cell apoptosis, and interfere the cell cycle in vitro. EIF3B-knockdown cells could form smaller subcutaneous tumors in vivo. Finally, we demonstrated EIF3B could activate β-catenin signaling pathway.
METHODS: Immunohistochemical staining and Western blot were performed to detect the EIF3B expression in ESCC patient tissues and cell lines. The association between EIF3B expression and patients' prognosis was analyzed by Kaplan-Meier and Cox regression. Then, CCK-8, colony-formation, Transwell and wound-healing assay were performed to compare the bio-functional change after knockdown of EIF3B. Flow cytometry was applied to analyze the change of cell apoptosis and cycle induced by EIF3B knockdown. Tumor xenograft assay was done to verify the in-vitro results.
CONCLUSIONS: EIF3B might serve as a novel marker for predicting prognosis of ESCC patients and as a potential therapeutic target, individually or together with other subunits of EIF3 complex.

Lin S, Choe J, Du P, et al.
The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.
Mol Cell. 2016; 62(3):335-345 [PubMed] Article available free on PMC after 15/02/2020 Related Publications
METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N(6)-methyladenosine (m(6)A) modification. Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. In contrast to current models that invoke m(6)A reader proteins downstream of nuclear METTL3, we find METTL3 associates with ribosomes and promotes translation in the cytoplasm. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. METTL3 expression is elevated in lung adenocarcinoma and using both loss- and gain-of-function studies, we find that METTL3 promotes growth, survival, and invasion of human lung cancer cells. Our results uncover an important role of METTL3 in promoting translation of oncogenes in human lung cancer.

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