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While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression. Synopsis: PD-L1 is a key immune checkpoint and largely affects the response of patients to immunotherapy. This study identifies ependymin-related protein 1 (EPDR1) as a potent regulator of PD-L1 expression in hepatocellular carcinoma (HCC), facilitating immune evasion. Aberrant expression of EPDR1 in HCC is associated with immunosuppression. Tumor-intrinsic EPDR1 facilitates immune evasion by increasing anti-tumor CD8 + T cells exhaustion. EPDR1 enhances the NF-κB pathway and elevates PD-L1 expression in cancer cells by interfering with TRIM21-dependent degradation of IkappaB kinase-b. EPDR1-TRIM21-PD-L1 axis promotes tumor immune evasion in HCC. A tumor-intrinsic EPDR1-TRIM21-PD-L1 axis promotes CD8 + T cells exhaustion in liver cancer. [ABSTRACT FROM AUTHOR]

Abstract Breast carcinoma (BC) ranks as a predominant malignancy and constitutes the second principal cause of mortality among women globally. Epirubicin stands as the drug of choice for BC therapeutics. Nevertheless, the emergence of chemoresistance has significantly curtailed its therapeutic efficacy. The resistance mechanisms to Epirubicin remain not entirely elucidated, yet they are conjectured to stem from diminished tumor vascular perfusion and resultant hypoxia consequent to Epirubicin administration. In our investigation, we meticulously scrutinized the Gene Expression Omnibus database for EPDR1, a gene implicated in hypoxia and Epirubicin resistance in BC. Subsequently, we delineated the impact of EPDR1 on cellular proliferation, motility, invasive capabilities, and interstitial-related proteins in BC cells, employing methodologies such as the CCK-8 assay, Transwell assay, and western blot analysis. Our research further unveiled that hypoxia-induced miR-181a-5p orchestrates the regulation of BC cell duplication, migration, invasion, and interstitial-related protein expression via modulation of EPDR1. In addition, we identified TRPC1, a gene associated with EPDR1 expression in BC, and substantiated that EPDR1 influences BC cellular dynamics through TRPC1-mediated modulation of the PI3K/AKT signaling cascade. Our findings underscore the pivotal role of EPDR1 in the development of BC. EPDR1 was found to be expressed at subdued levels in BC tissues, Epirubicin-resistant BC cells, and hypoxic BC cells. The overexpression of EPDR1 curtailed BC cell proliferation, motility, invasiveness, and the expression of interstitial-related proteins. At a mechanistic level, the overexpression of hypoxia-induced miR-181a-5p was observed to inhibit the EPDR1/TRPC1 axis, thereby activating the PI3K/AKT signaling pathway and diminishing the sensitivity to Epirubicin in BC cells. In summation, our study demonstrates that the augmentation of hypoxia-induced miR-181a-5p diminishes Epirubicin sensitivity in BC cells by attenuating EPDR1/TRPC1 expression, thereby invigorating the PI3K/AKT signaling pathway. This exposition offers a theoretical foundation for the application of Epirubicin in BC therapy, marking a significant contribution to the existing body of oncological literature.

Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the second and third most strongly associated ones (P = 6.4 × 10−132 and P = 9.2 × 10−69, respectively). For the most strongly associated Neandertal variant, we identify EPDR1 as the causal gene. Dupuytren's disease is an example of how admixture with Neandertals has shaped regional differences in disease prevalence. [ABSTRACT FROM AUTHOR]

Background: Bladder carcinoma is a common malignancy of the urinary system. The previous study showed that EPDR1 expression was significantly related to the carcinogenesis and progression of bladder carcinoma Methods: We retrospectively reviewed the records of 621 patients who were newly diagnosed with bladder carcinoma between January 2018 and August 2020 at The Affiliated Hospital of Zunyi Medical University. We conducted immunohistochemistry of EPDR1 in tumor tissues. Meanwhile, tumor budding evaluation was also carried out by 2 independent experienced pathologists. Results: 80 patients were included in this study with a median age of 66 years (range; 42-88 years). 45% of the patients (36/80) were non-muscleinvasive bladder carcinoma patients, while 55% of muscle-invasive bladder carcinoma(44/80). The follow-up time was from 6 months to 36 months. We found that there were significant differences in expression of EPDR1 in the tumor pT stages(p<0.05), pM stages(p<0.05), and pN stages(p<0.05). Meanwhile, a higher expression of EPDR1 indicated a worse outcome for the patient(p<0.05). A tendency toward a worse status of the patient was accompanied by a high positive rate (p<0.001). Moreover, the IOD of EPDR1 had a positive relationship with TB (p<0.05). Furthermore, we found that EPDR1 and tumor budding could be crucial factors for affecting the prognosis of bladder carcinoma, even better than pTMN(Riskscore=(0.724) * pT_stage +(4.960) *EPDR1+(4.312)*TB). Conclusion: In conclusion, bladder cancer patients with higher expression levels of EPDR1 had worse survival outcomes. The combination of TB and EPDR1 levels could predict the prognosis for muscle-invasive bladder cancer patients. [ABSTRACT FROM AUTHOR]

Abstract Background Bladder cancer (BLCA) is a malignant urothelial carcinoma and has a high mortality rate. EPDR1 (ependymin related 1) is a type II transmembrane protein and related to calcium-dependent cell adhesion. Methods We explored the potential oncogenic roles of EPDR1 in BLCA basing on the multiple public datasets. Results We found that EPDR1 expression had a significant difference in BLCA and adjacent normal bladder tissues, and the level of EPDR1was up-regulated with advanced tumor stage and metastasis in BLCA. Meanwhile, the high expression group of EPDR1 had a shorter OS compared to the low or medium expression-group. Furthermore, EPDR1 expression was associated with tumor-infiltrating immune cells (TIICs), including NK cells, CD8 + T cells, CD4 + T cells, Macrophages cells, and so on. Moreover, EPDR1 also involved in several signaling pathways as well as PI3K/AKT pathway, Cytokine receptor interaction, and apoptosis. Conclusion EPDR1 can be used as a novel prognostic biomarker as well as an effective target for diagnosis and treatment in BLCA.

Acute myeloid leukaemia (AML) is a blood cancer with a heterogeneous genomic landscape. This study aimed to mine bioinformatics data generated by RNA sequencing to unveil an AML case transcriptome profile and identify novel therapeutic targets and markers. In this study, we have determined the transcriptomic profile and analysed gene variants of an AML patient at the time of diagnosis and validated some genes by quantitative reverse transcriptase polymerase chain reaction. ADAMTS14, ARHGAP22, and ependymin-related protein 1 (EPDR1) were markedly upregulated compared to the corresponding control. In addition, novel exonic single-nucleotide and insertion/deletion variants were identified in these genes. Hence, ADAMTS14, ARHGAP22, and EPDR1 can be proposed as potential novel targets in AML, and their exact roles should be further explored.

Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future.

Background: Bladder cancer (BLCA) is a malignant urothelial carcinoma and has a high mortality rate. EPDR1 (ependymin related 1) is a type II transmembrane protein and related to calcium-dependent cell adhesion.Methods: We explored the potential oncogenic roles of EPDR1 in BLCA basing on the multiple public datasets.Results: We found that EPDR1 expression had a significant difference in BLCA and adjacent normal bladder tissues, and the level of EPDR1was up-regulated with advanced tumor stage and metastasis in BLCA. Meanwhile, the high expression group of EPDR1 had a shorter OS compared to the low or medium expression-group. Furthermore, EPDR1 expression was associated with tumor-infiltrating immune cells (TIICs), including NK cells, CD8 + T cells, CD4 + T cells, Macrophages cells, and so on. Moreover, EPDR1 also involved in several signaling pathways as well as PI3K/AKT pathway, Cytokine receptor interaction, and apoptosis.Conclusion: EPDR1 can be used as a novel prognostic biomarker as well as an effective target for diagnosis and treatment in BLCA. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has high mortality rate and is a serious disease burden globally. EPDR1 (ependymin related 1) is a member of piscine brain glycoproteins and is involved in cell adhesion. The gene expression, prognostic, and clinicopathological related data for EPDR1 were obtained from multiple transcriptome databases. Protein level of EPDR1 in HCC was verified using human protein atlas and CPTAC databases. EPDR1 co‐expressed genes were identified using LinkedOmics. Functional analysis of the co‐expressed genes was performed using gene set enrichment analysis, Gene Ontology, and KEGG. Statistical analysis was conducted in R. The relationship between EPDR1 expression and immune cell infiltration was analyzed using TIMER and CIBERSORT. The expression of EPDR1 was found to be significantly higher in HCC than in normal tissues. Further, EPDR1 level was correlated with advanced stage of HCC. EPDR1 was associated with multiple signaling, as well as cancer and apoptotic pathways. Further, EPDR1 expression was significantly correlated with purity and infiltration levels of various immune cells as well as immune signatures. This is the first study to report the role of EPDR1 in HCC. EPDR1 can be used as a novel prognostic biomarker as well as an effective target for diagnosis and treatment in HCC. [ABSTRACT FROM AUTHOR]

Background: Bladder carcinoma is a common malignancy of the urinary system. The previous study showed that EPDR1 expression was significantly related to the carcinogenesis and progression of bladder carcinoma., Methods: We retrospectively reviewed the records of 621 patients who were newly diagnosed with bladder carcinoma between January 2018 and August 2020 at The Affiliated Hospital of Zunyi Medical University. We conducted immunohistochemistry of EPDR1 in tumor tissues. Meanwhile, tumor budding evaluation was also carried out by 2 independent experienced pathologists., Results: 80 patients were included in this study with a median age of 66 years (range; 42-88 years). 45% of the patients (36/80) were non-muscle-invasive bladder carcinoma patients, while 55% of muscle-invasive bladder carcinoma(44/80). The follow-up time was from 6 months to 36 months. We found that there were significant differences in expression of EPDR1 in the tumor pT stages(p<0.05), pM stages(p<0.05), and pN stages(p<0.05). Meanwhile, a higher expression of EPDR1 indicated a worse outcome for the patient(p<0.05). A tendency toward a worse status of the patient was accompanied by a high positive rate (p<0.001). Moreover, the IOD of EPDR1 had a positive relationship with TB (p<0.05). Furthermore, we found that EPDR1 and tumor budding could be crucial factors for affecting the prognosis of bladder carcinoma, even better than pTMN(Riskscore=(0.724)* pT&#95;stage +(4.960) *EPDR1+(4.312)*TB)., Conclusion: In conclusion, bladder cancer patients with higher expression levels of EPDR1 had worse survival outcomes. The combination of TB and EPDR1 levels could predict the prognosis for muscle-invasive bladder cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Xu, Zhu, Yuan, Zhang, Liu, Zhao and Liang.)

Background: EPDR1 is widely expressed in cancer, especially colorectal cancer. However, the biologic function of EPDR1 in breast cancer is uncertain., Methods: The expression profile of EPDR1 was assessed by Gene Expression Profiling Interactive Analysis ( GEPIA ; gepia.cancer-pku.cn). We constructed EPDR1-overexpressing (EPDR1-Ov) plasmids that were transfected into breast cancer cells (MCF-7 and MDA-MB-453) to examine the EPDR1 effect on their malignant behavior. The EPDR1 overexpression and the critical components of the P53 signaling pathway were determined by western blot or RT-PCR. Cell proliferation, colony formation, invasive capacity, and cell apoptotic proportions were examined after transfection., Results: mRNA expression of EPDR1 was significantly lessened in breast cancer tissues when compared to the adjacent normal tissues by data analysis from GEPIA. There was an impairment in proliferative ability, viability, invasion, and anti-apoptotic effect in EPDR1 overexpressed breast cancer cells. Mechanistic studies showed that EPDR1 overexpression increased the p53, p21 and Bcl-2 expression while inhibiting Bax expression., Conclusion: EPDR1 inhibited malignant behaviors and promoted apoptosis in breast cancer cells by activation of the p53 signaling pathway., Competing Interests: None., (IJCEP Copyright © 2020.)