Involvement of microRNA-718, a new regulator of EGR3, in regulation of malignant phenotype of HCC cells

Wang, Zhongdong; Qu, Fanyong; Chen, Yuanyuan; Ran, Zhangshen; Liu, Haiyan; Zhang, Haidong

doi:10.1631/jzus.b1600205

Cited by 25 publications

(19 citation statements)

References 21 publications

(24 reference statements)

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“…We found an increase in EGR3 protein expression in migrating tumour cells in the periphery, suggesting that EGR3 plays a role in tumour cell migration, thereby indirectly causing accelerated tumour progression, which leads to poor patient outcome. Supporting this hypothesis, a decline of EGR3 expression has been shown to decrease motility of non-small cell lung cancer cells 39 , while EGR3 has been associated with migration and invasion in hepatocellular 40,41 and breast carcinomas 21 .…”

Section: Discussionmentioning

confidence: 88%

Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas

Knudsen

Eilertsen

Kielland

et al. 2020

Sci Rep

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Most glioblastoma patients have a dismal prognosis, although some survive several years. However, only few biomarkers are available to predict the disease course. EGR1 and EGR3 have been linked to glioblastoma stemness and tumour progression, and this study aimed to investigate their spatial expression and prognostic value in gliomas. Overall 207 gliomas including 190 glioblastomas were EGR1/EGR3 immunostained and quantified. A cohort of 21 glioblastomas with high P53 expression and available tissue from core and periphery was stained with double-immunofluorescence (P53-EGR1 and P53-EGR3) and quantified.EGR1 expression increased with WHO-grade, and declined by 18.9% in the tumour periphery vs. core (P = 0.01), while EGR3 expression increased by 13.8% in the periphery vs. core (P = 0.04). In patients with high EGR1 expression, 83% had methylated MGMT-promoters, while all patients with low EGR1 expression had un-methylated MGMT-promoters. High EGR3 expression in MGMT-methylated patients was associated with poor survival (HR = 1.98; 95%CI 1.22-3.22; P = 0.006), while EGR1 high/EGR3 high, was associated with poor survival vs. EGR1 high/EGR3 low (HR = 2.11; 95%CI 1.25-3.56; P = 0.005). EGR1 did not show prognostic value, but could be involved in MGMTmethylation. Importantly, EGR3 may be implicated in cell migration, while its expression levels seem to be prognostic in MGMT-methylated patients. Gliomas are the most common primary brain tumours, with the WHO grade IV glioblastoma multiforme (GBM) being the most malignant. In GBMs the current standard treatment with radical surgical resection, radiation and temozolomide therapy results in a median survival of approximately 15 months 1-3 , although some patients survive several years after diagnosis. Only few prognostic biomarkers are of use in daily practise, like the methylation status of O-6-Methylguanine-DNA Methyltransferase (MGMT) 4 and mutational status of the Isocitrate dehydrogenase 1/2 genes 5. Identification of additional novel biomarkers is therefore crucial in order to better stratify the patients. GBMs are characterized as highly vascularized, heterogeneous tumours with a profoundly infiltrative nature, leading to accelerated and aggressive disease progression. Nearly all GBMs recur after initial treatment efforts due to migrating tumour cells, which infiltrate the adjacent healthy brain parenchyma and escape surgical excision as well as radiation and temozolomide therapy. We have previously shown that these migrating tumour cells have a stem-cell like phenotype and are highly tumourigenic in vivo 6. Early growth response protein 1 (EGR1) and Early growth response protein 3 (EGR3) are C2H2-type zinc-finger proteins, which belong to the EGR-protein family of transcription factors. EGR1 has been proposed to regulate the expression of genes involved in cell proliferation, growth and cell differentiation 7,8. In addition, EGR3 has been implicated in immune regulation 9-11 and cell migration 12,13. Recently, EGR1 has been linked to the proliferation and self-rene...

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Section: Discussionmentioning

confidence: 88%

Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas

Knudsen

Eilertsen

Kielland

et al. 2020

Sci Rep

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“…As previously reported, EGR1 plays multiple tumor suppressor roles in breast cancer, in which its expression is often lost ( Crawford et al, 2019 ); EGR2 is a growth inhibitor when upregulated in tumor cells ( Salotti et al, 2015 ), exogenous expression of EGR2 can also suppress the growth of tumor cells ( Unoki and Nakamura, 2003 ), but its role in breast cancer is rarely reported; downregulation of EGR3 can promote the migration and invasion of hepatocellular carcinoma (HCC) ( Wangdong et al, 2017 ), high expression level of EGR3 was discovered in prostate cancer samples ( Pio et al, 2013 ), but its role in breast cancer is also rarely reported. Few researches reported EGR4 in malignant tumors; only some articles reported that EGR4 might promote NSCLC ( He et al, 2019 ), small cell lung cancer (SCLC) ( Matsuo et al, 2014 ), and cholangiocarcinoma (CHOL) to develop ( Gong et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Risk Prediction Model for Breast Cancer Based on Immune Genes Related to Early Growth Response Proteins Family

Zhou

Zhang

Liu

et al. 2021

Front. Mol. Biosci.

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Early growth response proteins (EGRs), a transcriptional regulatory family comprised of EGR1, EGR2, EGR3, and EGR 4, are reportedly involved in a vast array of functions. However, EGRs, as a whole, are rarely studied in breast cancer cases. This research was performed based on public datasets. The results demonstrated that, except EGR4, the other EGRs were differentially expressed genes in breast cancer. Subsequently, this study determined the prognosis significance of the EGR family, higher expression levels of EGRs indicating better overall survival (OS) and disease-free survival (DFS), except EGR4. So we attempted to explore the potential mechanism behind the prognostic value of EGRs. At the DNA level, however, neither DNA methylation status nor genetic alterations of EGRs contributed to the prognosis significance. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that EGRs were involved in several immune-related functions. Afterward, we assessed the correlation between EGRs and the immune system before establishing a risk prediction model with a 14-gene immune signature associated with EGRs, a prognostic nomogram predicting individuals’ 1-, 3-, and 5-year survival probabilities. The risk score was an independent prognosis predictor in the breast cancer cohorts. This study evidenced EGRs’ significance for tumor immunity, demonstrating that the EGR family may be a potential immunotherapeutic target for breast cancer. The 14-gene immune signature is a promising prognostic biomarker in breast cancer.

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“…miRNAs can regulate numerous genes at the post-transcriptional level, and the aberrant expression of miRNAs is closely associated with the development of neoplasms in humans (36). Recently, a substantial number of cancer-specific miRNAs have been identified as tumor biomarkers in various types of cancer (37,38).…”

Section: Discussionmentioning

confidence: 99%

Overexpressing miR‑335 inhibits DU145 cell proliferation by targeting early growth response 3 in prostate cancer

et al. 2019

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MicroRNA-335 (miR-335) was reported to suppress cell proliferation in prostate cancer (PC), a common malignancy in males. The expression of early growth response 3 (EGR3) was determined to be elevated in human PC tissues; however, the possible effects and underlying mechanism of miR-335 on PC remains unknown. In the present study, miR-335 mimics and miR-335 inhibitors were respectively transfected into DU145 cells. Stable silencing of EGR3 was observed in DU145 cells following transfection with small interfering RNA. We also used Cell Counting Kit-8 and in vitro angiogenesis assays to determine the viability and revascularization potential of DU145 cells. The expression levels of EGR and caspase-3 activity were analyzed by immunohistochemistry and immunocytochemistry, respectively. We predicted the target of miR-335 by bioinformatics analysis and a dual-luciferase reporter gene assay. Western blot and quantitative real-time polymerase chain reaction analyses were performed to determine the protein and mRNA expression of molecules. miR-335 expression was downregulated in PC tissues and cell lines. Overexpression of miR-335 significantly reduced the viability and the formation of regenerative tubes of DU145 cells, and inhibited the expression of inflammatory factors. EGR3 was proposed as a possible target of miR-335, and was negatively regulated by miR-335. Silencing EGR3 suppressed the viability and angiogenesis of DU145 cells, and reduced the activity of caspase-3 and inflammatory factor expression. miR-335 inhibition along with EGR3 silencing EGR3 inhibited the cell proliferation. Furthermore, miR-335 inhibited the formation of a PC solid tumor xenograft in vivo . Thus, miR-335 may exert an antitumor effect on DU145 cells by regulating the expression of EGR3. The findings of the present study may provide insight into a novel therapeutic strategy for the treatment of prostatic carcinoma.

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Involvement of microRNA-718, a new regulator of EGR3, in regulation of malignant phenotype of HCC cells

Cited by 25 publications

References 21 publications

Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas

Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas

A Risk Prediction Model for Breast Cancer Based on Immune Genes Related to Early Growth Response Proteins Family

Overexpressing miR‑335 inhibits DU145 cell proliferation by targeting early growth response 3 in prostate cancer

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