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<p>Radiotherapy is the standard adjuvant treatment for hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) have been identified as the primary factor contributing to radiation resistance. Astrocyte elevated gene-1 (AEG-1) could regulate β-catenin signaling to maintain tumor stem-like stemness and self-renewal. This study aims to explore the role and mechanism of AEG-1 in the radioresistance of HCC. The mRNA levels of AEG-1 and FOXP1 were determined using RT-qPCR. AEG-1, FOXP1, Oct4, CD133, Nanog, β-catenin, and c-Myc protein levels were detected using western blot. The radiosensitivity of HCC cells was assessed using cell colony formation assay, γ-H2AX immunofluorescence, and flow cytometry. The CSC characteristics of cells were examined using sphere formation assay. The biological role of AEG-1 on HCC tumor growth and radiation resistance was examined by the mouse xenograft tumor model<i>.</i> Correlation between AEG-1 and FOXP1 in HCC patients was analyzed using Pearson correlation analysis. Binding between FOXP1 and AEG-1 promoter was predicted by JASPAR and verified by ChIP, the electrophoretic mobility shift assays (EMSA), and dual-luciferase reporter assays. AEG-1 was highly expressed in HCC patients, and positively associated with FOXP1 expression. Moreover, AEG-1 knockdown could enhance the radiosensitivity of HCC cells by promoting ionizing radiation (IR)-DNA damage and apoptosis in vitro. AEG-1 mediated radiation resistance by maintaining HCC tumor stem cell properties. In vivo investigation revealed that AEG-1 silencing repressed HCC tumor growth and increased radiosensitivity. Mechanistically, FOXP1 was a transcription factor of AEG-1 that promoted AEG-1 transcription by binding to its promoter region. FOXP1 promoted the Wnt/β-catenin pathway by regulating AEG-1. Overall,&#xa0;overexpressing FOXP1 drives stem cell properties and radioresistance of HCC cells by promoting AEG-1-mediated Wnt/β-catenin pathway, providing a promising therapeutic target for enhancing radiotherapy efficacy.</p>

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FOXP1-transcriptionally regulated AEG-1 enhances tumor cell stemness to promote hepatocellular carcinoma radioresistance

  • 期刊论文

  • 发表日期：

    2025年10月28日

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  • Weizhi Li,
  • Hui Xue,
  • Peijie Li,
  • Xiaozhi Zhang

摘要

Radiotherapy is the standard adjuvant treatment for hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) have been identified as the primary factor contributing to radiation resistance. Astrocyte elevated gene-1 (AEG-1) could regulate β-catenin signaling to maintain tumor stem-like stemness and self-renewal. This study aims to explore the role and mechanism of AEG-1 in the radioresistance of HCC. The mRNA levels of AEG-1 and FOXP1 were determined using RT-qPCR. AEG-1, FOXP1, Oct4, CD133, Nanog, β-catenin, and c-Myc protein levels were detected using western blot. The radiosensitivity of HCC cells was assessed using cell colony formation assay, γ-H2AX immunofluorescence, and flow cytometry. The CSC characteristics of cells were examined using sphere formation assay. The biological role of AEG-1 on HCC tumor growth and radiation resistance was examined by the mouse xenograft tumor model. Correlation between AEG-1 and FOXP1 in HCC patients was analyzed using Pearson correlation analysis. Binding between FOXP1 and AEG-1 promoter was predicted by JASPAR and verified by ChIP, the electrophoretic mobility shift assays (EMSA), and dual-luciferase reporter assays. AEG-1 was highly expressed in HCC patients, and positively associated with FOXP1 expression. Moreover, AEG-1 knockdown could enhance the radiosensitivity of HCC cells by promoting ionizing radiation (IR)-DNA damage and apoptosis in vitro. AEG-1 mediated radiation resistance by maintaining HCC tumor stem cell properties. In vivo investigation revealed that AEG-1 silencing repressed HCC tumor growth and increased radiosensitivity. Mechanistically, FOXP1 was a transcription factor of AEG-1 that promoted AEG-1 transcription by binding to its promoter region. FOXP1 promoted the Wnt/β-catenin pathway by regulating AEG-1. Overall, overexpressing FOXP1 drives stem cell properties and radioresistance of HCC cells by promoting AEG-1-mediated Wnt/β-catenin pathway, providing a promising therapeutic target for enhancing radiotherapy efficacy.