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Epidermal growth factor receptor pathway substrate 8 (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which is involved in cell mitosis, differentiation and other physiological functions. Numerous studies over the last decade have demonstrated that Eps8 is overexpressed in most ubiquitous malignant tumours and subsequently binds with its receptor to activate multiple signalling pathways. Eps8 not only participates in the regulation of malignant phenotypes, such as tumour proliferation, invasion, metastasis and drug resistance, but is also related to the clinicopathological characteristics and prognosis of patients. Therefore, Eps8 is a potential tumour diagnosis and prognostic biomarker and even a therapeutic target. This review aimed to describe the structural characteristics, role and related molecular mechanism of Eps8 in malignant tumours. In addition, the prospect of Eps8 as a target for cancer therapy is examined.

Esophageal cancer is one of the fatal cancers around the world. Dexmedetomidine (DEX) is widely used during anesthesia of esophageal cancer surgery. Nevertheless, the role of DEX in the progression of esophageal cancer remains barely known. The proliferation, apoptosis and metastasis of esophageal cancer cells were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, transwell migration and invasion assays and Western blot assay. The expression of miR-143-3p was measured by quantitative real-time PCR in esophageal cancer tissues and cells. The binding sites between miR-143-3p and epidermal growth factor receptor pathway substrate 8 (EPS8) were predicted by Starbase online software, and the combination was verified by dual-luciferase reporter assay. The murine xenograft model was established using KYSE150 cells to verify the function of DEX in vivo. DEX inhibited the proliferation and metastasis while accelerated the apoptosis of esophageal cancer cells. The abundance of miR-143-3p was lower in esophageal cancer tissues and cells than that in paring normal tissues and normal esophageal mucosal cells Het-1A. MiR-143-3p could be induced by DEX treatment in esophageal cancer cells, and miR-143-3p also suppressed the development of esophageal cancer. EPS8 was a functional target of miR-143-3p, and it played an oncogenic role in esophageal cancer. DEX inhibited the growth of tumor via miR-143-3p/EPS8 in vivo. DEX suppressed the growth and metastasis while facilitated the apoptosis of esophageal cancer cells through upregulating the abundance of miR-143-3p and reducing the level of EPS8 in vivo and in vitro, providing promising target for the treatment of esophageal cancer.

Epidermal growth factor receptor pathway substrate 8 (EPS8) is critical in the proliferation, progression and metastasis of solid and hematological types of cancer, and thus constitutes an ideal target for cancer immunotherapy. The present study aimed to identify human leukocyte antigen (HLA)‑A*1101‑restricted cytotoxic T lymphocyte (CTL) epitopes from EPS8 and characterize their immunotherapeutic efficacy in vitro. Two computer‑based algorithms were used to predict native EPS8 epitopes with potential high binding affinity to the HLA‑A*1101 molecule, which is the HLA‑A allele with the highest frequency in the Chinese population. The peptide‑induced cytokine production from the CTLs was examined using enzyme‑linked immunosorbent spot analysis. The cytotoxic effects on cancer cells by CTLs primed with the identified peptides were examined using flow cytometry. A total of five peptides, designated as P380, P70, P82, P30 and P529, presented with high affinity towards the HLA‑A*1101 molecule. In response to stimulation by these five peptides, enhanced secretion of interferon‑γ from the CTLs and increased cytolytic capabilities of the CTLs toward cancer cells were noted, with the most potent effects observed from the P380 peptide. Taken together, the present study identified five potential CTL epitopes from EPS8. Among these, P380 presented with the highest therapeutic efficacy in vitro. These peptides may benefit the development of EPS8‑based immunotherapy for the treatment of HLA‑A*1101‑positive hematological malignancies.

T-cell-mediated immunotherapy of hematological malignancies requires selection of targeted tumor-associated antigens and T-cell epitopes contained in these tumor proteins. Epidermal growth factor receptor pathway substrate 8 (EPS8), whose function is pivotal for tumor proliferation, progression and metastasis, has been found to be overexpressed in most human tumor types, while its expression in normal tissue is low. The aim of the present study was to identify human leukemia antigen (HLA)-A*0201-restricted epitopes of EPS8 by using a reverse immunology approach. To achieve this, computer algorithms were used to predict HLA-A*0201 molecular binding, proteasome cleavage patterns as well as translocation of transporters associated with antigen processing. Candidate peptides were experimentally validated by T2 binding affinity assay and brefeldin-A decay assay. The functional avidity of peptide-specific cytotoxic T lymphocytes (CTLs) induced from peripheral blood mononuclear cells of healthy volunteers were evaluated by using an enzyme-linked immunosorbent spot assay and a cytotoxicity assay. Four peptides, designated as P455, P92, P276 and P360, had high affinity and stability of binding towards the HLA-A*0201 molecule, and specific CTLs induced by them significantly responded to the corresponding peptides and secreted IFN-γ. At the same time, the CTLs were able to specifically lyse EPS8-expressing cell lines in an HLA-A*0201-restricted manner. The present study demon-strated that P455, P92, P276 and P360 were CTL epitopes of EPS8, and were able to be used for epitope-defined adoptive T-cell transfer and multi-epitope-based vaccine design.

International audience; BACKGROUND: Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness. METHOD: Whole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved. RESULTS: A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8-/- mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia. CONCLUSION: This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.

To analyze the epidermal growth factor receptor pathway substrate 8 (EPS8) expression status and role in colorectal carcinogenesis given that EPS8 has a conserved actin barbed-end capping function that is required for proper maturation in intestinal cells.We studied 8 colon cancer cell lines and 58 colorectal tumors (19 adenomas and 39 carcinomas). We performed expression microarray analysis of colon cancer cell lines followed by loss of heterozygosity (LOH) analysis and immunohistochemistry for EPS8 expression in colon tumors. Subsequently, we performed mutation analysis by direct sequencing and methylation analysis by bisulfite sequencing and methylation-specific polymerase chain reaction assays.Expression microarray analysis of colon cancer cell lines showed overexpression of EPS8 transcript in all lines but RKO. Genome wide loss of heterozygosity (LOH) analysis of colon tumors, showed considerable LOH at the EPS8 gene locus. Immunohistochemically, EPS8 was constitutively expressed in normal colonic mucosa with a dot-like supranuclear localization with accentuation at the luminal surface supporting its proposed role in epithelial maturation. Nineteen colon tumors (4 adenoma, 15 carcinoma) out of 51 (37%) showed strikingly tumor specific EPS8 protein loss. Of the remaining tumors, 5/51 (2 adenoma, and 3 carcinoma, 10%) showed marked overexpression, while 27/51 tumors (53%) showed retained expression. Mutation analysis revealed a missense mutation (c.794CT, p.R265C) in exon 8 in RKO. The EPS8 promoter was also methylated in RKO, but there was no significant methylation in other cell lines or carcinoma specimens.The loss of EPS8 expression in colorectal adenomas and carcinomas suggests that down regulation of this gene contributes to the development of a subset of colorectal cancers, a finding which could have applications in diagnosis and treatment.