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Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer

Cancer Gene Therapy (2024)Cite this article

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Abstract

EGR4 (Early Growth Response 4) is a member of the EGR family, involving in tumorigenesis. However, the function and action mechanism of EGR4 in the pathogenesis of colorectal cancer (CRC) remain unclear. To address this, we assessed the prognosis of CRC based on EGR4 using the Kaplan-Meier plotter tool and tissue microarray. The abundance of immunoinfiltration was evaluated through ssGSEA, TISIDB, and TIMER. In vitro experiments involving knockdown or overexpression of EGR4 were performed, and RNA-sequencing was conducted to explore potential mechanisms. Furthermore, we used oxaliplatin and 5-fluorouracil to validate the impact of EGR4 on chemo-resistance. Pan-cancer analysis and tissue microarray showed that EGR4 was highly expressed in CRC and significantly correlated with an unfavorable prognosis. Moreover, EGR4 expression was associated with immunoinfiltration and cancer-associated fibroblasts in the CRC microenvironment. Functional enrichment demonstrated that high-expressional EGR4 were involved in chromatin and nucleosome assembly. Additionally, EGR4 promoted the proliferation of CRC cells. Mechanistically, EGR4 upregulated TNFα to activate the NF-κB signaling pathway, and its knockdown reduced p65 nuclear translocation. Importantly, combining shEGR4 with oxaliplatin and 5-fluorouracil significantly inhibited CRC proliferation. Taken together, these findings provide new insights into the potential prognosis and therapeutic targets of EGR4 in CRC.

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Fig. 1: High-expressional EGR4 as a novel biomarker and prognostic indicator in colorectal cancer.
Fig. 2: Correlation of immunoinfiltration, CAFs, and EGR4 expression in CRC patients.
Fig. 3: DEGs and functional enrichment analysis between EGR4 high and low-expressional group.
Fig. 4: High-expressional EGR4 indicated poor prognosis in CRC patients.
Fig. 5: EGR4 contributed to the proliferation of CRC in vitro.
Fig. 6: High expression of EGR4 increased the chemoresistance of CRC in vitro.
Fig. 7: EGR4 activated TNFɑ/NF-κB signaling pathway by bioinformatics and functional enrichment analysis in CRC.

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Data availability

The datasets generated and analyzed during this study are available in the public database TCGA.

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Acknowledgements

Thanks GEO and TEGA for sufficient RNA-sequencing data and clinical information.

Funding

This research was supported by grants from The National Natural Science Foundation of China (82202828, 82000621). Ili Kazakh Autonomous Clinical Research Institute (yl2020ms10). Key Project of GuSu College, Nanjing Medical University (GSKY20220109).

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  1. These authors contributed equally: Bangting Wang, Shijie Zhang.

Authors and Affiliations

  1. Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University and Jiangsu Province Hospital, Nanjing, Jiangsu, China

    Bangting Wang, Shijie Zhang, Haiyang Wang, Min Wang, Yuwen Tao, Mujie Ye, Zhining Fan, Yan Wang & Li Liu

  2. The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Yining, China

    Bangting Wang & Yan Wang

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Contributions

Bangting Wang, Yan Wang and Li Liu designed the experiments; Bangting Wang, Shijie Zhang and Jiankun Wang performed the experiments; Bangting Wang and Shijie Zhang prepared all figures; Bangting Wang, Shijie Zhang and Haiyang Wang analyzed the data; Zhining Fan and Li Liu supervised the work; Bangting Wang, Jiangkun Wang, Yuwen Tao and Shijie Zhang wrote the manuscript.

Corresponding authors

Correspondence to Yan Wang or Li Liu.

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Ethics statement and consent to participate

Data from the TCGA and GTEx databases were used in our study. Our research involves human tissues derived from tumor and adjacent normal tissues of CRC patients. All patients signed an informed consent form. Ethical approval for this study was obtained from the Ethical Committee of Medical Research, Jiangsu Province Hospital of Nanjing Medical University (2018-SR-258). There are no clinical trials or animal experiments in our research.

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Wang, B., Zhang, S., Wang, H. et al. Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00743-1

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