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<p>Cisplatin is mainly used for treating terminal hepatocellular carcinoma (HCC), but the development of drug resistance limits its clinical efficacy in treating this disease. The helicase activity of DDX11 can prevent hypersensitivity to chemotherapy drugs and DNA damage. The aim of this study was to explore the potential molecular mechanism through which DDX11 mediates cisplatin resistance in HCC. HepG2 and Huh7 cisplatin-resistant strains were established and named HepG2-DDP and Huh7-DDP, respectively. Cell proliferation and DNA damage were measured by CCK-8, colony formation and comet assays, and the expression of related proteins and genes was detected by Western blotting, immunohistochemistry, immunofluorescence and RT‒qPCR. The HepG2-DDP and Huh7-DDP cell lines were xenografted subcutaneously into nude mice to investigate the role of DDX11 in vivo. DDX11 expression was upregulated in HCC clinical samples and cell lines. <i>DDX11</i> knockdown inhibited HCC cell proliferation and promoted sensitivity to cisplatin, DNA damage and endoplasmic reticulum (ER) stress, and <i>SKP2</i> knockdown weakened the effects of <i>DDX11</i> overexpression and promoted cisplatin-induced ER stress. Mechanistically, DDX11 inhibited cisplatin-induced DNA damage and ER stress by upregulating SKP2 expression, ultimately reducing the sensitivity of HCC cells to cisplatin. This study revealed that the DDX11/SKP2 axis may be a promising therapeutic target for improving resistance to cisplatin in patients with HCC.</p>

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DDX11/SKP2 Inhibits Cisplatin Sensitivity in Liver Cancer Cells by Regulating DNA Damage Repair and ER Stress

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • Shujia Kong,
  • Xin Pan,
  • Jiaxun Li,
  • Chen Zhao,
  • Yanwen Li

摘要

Cisplatin is mainly used for treating terminal hepatocellular carcinoma (HCC), but the development of drug resistance limits its clinical efficacy in treating this disease. The helicase activity of DDX11 can prevent hypersensitivity to chemotherapy drugs and DNA damage. The aim of this study was to explore the potential molecular mechanism through which DDX11 mediates cisplatin resistance in HCC. HepG2 and Huh7 cisplatin-resistant strains were established and named HepG2-DDP and Huh7-DDP, respectively. Cell proliferation and DNA damage were measured by CCK-8, colony formation and comet assays, and the expression of related proteins and genes was detected by Western blotting, immunohistochemistry, immunofluorescence and RT‒qPCR. The HepG2-DDP and Huh7-DDP cell lines were xenografted subcutaneously into nude mice to investigate the role of DDX11 in vivo. DDX11 expression was upregulated in HCC clinical samples and cell lines. DDX11 knockdown inhibited HCC cell proliferation and promoted sensitivity to cisplatin, DNA damage and endoplasmic reticulum (ER) stress, and SKP2 knockdown weakened the effects of DDX11 overexpression and promoted cisplatin-induced ER stress. Mechanistically, DDX11 inhibited cisplatin-induced DNA damage and ER stress by upregulating SKP2 expression, ultimately reducing the sensitivity of HCC cells to cisplatin. This study revealed that the DDX11/SKP2 axis may be a promising therapeutic target for improving resistance to cisplatin in patients with HCC.