Scholarlink

<p>Protein kinase D1 (PRKD1), a serine/threonine kinase of the PKD family, has been implicated in tumor biology, but its role in hepatocellular carcinoma (HCC) remains unclear. We explored PRKD1 expression and function using immunohistochemistry, bulk and single-cell RNA sequencing, and in vitro functional assays. PRKD1 protein levels were significantly elevated in 339 HCC tissues compared to corresponding adjacent non-tumorous samples (11.390 ± 1.560 vs. 6.277 ± 2.357, <i>P</i> &lt; 0.0001). Multicenter bulk transcriptomic data confirmed consistent PRKD1 mRNA overexpression (SMD = 0.26, 95% CI = 0.14–0.39), with single-cell transcriptomic profiling indicating specific enrichment in endothelial cells, smooth muscle cells, and hepatocytes. High PRKD1 expression was associated with advanced tumor stages and worse overall survival. Functionally, PRKD1-associated genes were enriched in extracellular matrix and focal adhesion pathways. Immune profiling revealed positive correlations with M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), and negative correlations with CD8<sup>+</sup> T cells and CD4<sup>+</sup> Th1 cells, suggesting an immunosuppressive role. Mechanistic experiments demonstrated that conditioned medium from PRKD1-knockdown HCC cells promoted M1 polarization and reduced M2 markers in THP-1 cells, while PRKD1 silencing increased PD-L1 and IDO1 expression. In contrast, IFN-γ treatment did not induce PRKD1 expression, indicating that PRKD1 actively contributes to, rather than responds to, immunosuppressive cues. PRKD1 knockdown markedly impaired HCC cell proliferation and migration. Pharmacologically, nitidine chloride significantly reduced PRKD1 expression in a dose-dependent manner, and molecular docking suggested a potential direct interaction. With respect to drug response, PRKD1-high HCC cases exhibited increased predicted sensitivity to multiple tyrosine kinase inhibitors (TKIs), while in vitro PRKD1 knockdown reduced sorafenib sensitivity, and sorafenib treatment suppressed both PRKD1 and p-ERK1/2 levels. Collectively, our findings identify PRKD1 as a multifaceted contributor to HCC progression, immune microenvironment modulation, and TKI responsiveness. These results highlight PRKD1 as a promising therapeutic target warranting further mechanistic and translational investigation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Overexpression, clinical significance and potential mechanisms of protein kinase D1 in hepatocellular carcinoma: multi-omic analyses and pharmacological insights

  • 期刊论文

  • 发表日期：

    2026年2月5日

查看全文
  • Zhen-dong Chen,
  • Hui-ping Lu,
  • Yan-ting Zhan,
  • Fei-yan He,
  • Liang-qin Zhu,
  • Yu-long Deng,
  • Xi-ni Wei,
  • Min-ying Yang,
  • Kai Qin,
  • Yu-xing Tang,
  • Ke-jun Wu,
  • Zhi-guang Huang,
  • Rong-quan He,
  • Gang Chen,
  • Yi-wu Dang

摘要

Protein kinase D1 (PRKD1), a serine/threonine kinase of the PKD family, has been implicated in tumor biology, but its role in hepatocellular carcinoma (HCC) remains unclear. We explored PRKD1 expression and function using immunohistochemistry, bulk and single-cell RNA sequencing, and in vitro functional assays. PRKD1 protein levels were significantly elevated in 339 HCC tissues compared to corresponding adjacent non-tumorous samples (11.390 ± 1.560 vs. 6.277 ± 2.357, P < 0.0001). Multicenter bulk transcriptomic data confirmed consistent PRKD1 mRNA overexpression (SMD = 0.26, 95% CI = 0.14–0.39), with single-cell transcriptomic profiling indicating specific enrichment in endothelial cells, smooth muscle cells, and hepatocytes. High PRKD1 expression was associated with advanced tumor stages and worse overall survival. Functionally, PRKD1-associated genes were enriched in extracellular matrix and focal adhesion pathways. Immune profiling revealed positive correlations with M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), and negative correlations with CD8+ T cells and CD4+ Th1 cells, suggesting an immunosuppressive role. Mechanistic experiments demonstrated that conditioned medium from PRKD1-knockdown HCC cells promoted M1 polarization and reduced M2 markers in THP-1 cells, while PRKD1 silencing increased PD-L1 and IDO1 expression. In contrast, IFN-γ treatment did not induce PRKD1 expression, indicating that PRKD1 actively contributes to, rather than responds to, immunosuppressive cues. PRKD1 knockdown markedly impaired HCC cell proliferation and migration. Pharmacologically, nitidine chloride significantly reduced PRKD1 expression in a dose-dependent manner, and molecular docking suggested a potential direct interaction. With respect to drug response, PRKD1-high HCC cases exhibited increased predicted sensitivity to multiple tyrosine kinase inhibitors (TKIs), while in vitro PRKD1 knockdown reduced sorafenib sensitivity, and sorafenib treatment suppressed both PRKD1 and p-ERK1/2 levels. Collectively, our findings identify PRKD1 as a multifaceted contributor to HCC progression, immune microenvironment modulation, and TKI responsiveness. These results highlight PRKD1 as a promising therapeutic target warranting further mechanistic and translational investigation.