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<p>Head and neck squamous cell carcinoma (HNSC) is a leading cause of morbidity and mortality worldwide. The roles of PHLDA genes in HNSC progression remain unclear. This study explores their expression, mutational landscape, and functional roles as potential diagnostic biomarkers and therapeutic targets. Eight HNSC cell lines and six normal oral keratinocyte cell lines were cultured, and RNA extraction and RT-qPCR analysis were conducted. The GSCA database validated gene expression in clinical HNSC samples. Methylation and survival analysis were performed using TCGA data, with survival correlation assessed via the KM Plotter tool and UALCAN database. Mutational analysis was done via cBioPortal, and immune-related correlations were analyzed using TISIDB. Functional assays were performed after siRNA-mediated knock down of PHLDA genes in SCC9 and SCC25 cells, including Western blot, CCK-8, colony formation, and wound healing assays. Our results demonstrate that PHLDA1, PHLDA2, and PHLDA3 are significantly upregulated in HNSC cell lines compared with normal controls, with PHLDA1 showing the most substantial increase. ROC analysis revealed that PHLDA1 exhibited the highest diagnostic potential for distinguishing HNSC from normal tissues. Methylation analysis showed hypomethylation of PHLDA genes in tumor tissues, particularly in the promoter regions. Higher expression of PHLDA genes correlated with poorer overall survival outcomes in HNSC patients. Mutational analysis revealed that PHLDA2 exhibited the highest mutation rate, with predominantly missense mutations. The PPI network analysis indicated that PHLDA genes interact with several cancer-related proteins, and DAVID analysis showed their involvement in processes like cell cycle regulation and tumorigenesis. Functional assays demonstrated that silencing of PHLDA genes in HNSC cells significantly impaired cell proliferation, clonogenic potential, and migration, suggesting their role as oncogenic regulators. Our study identifies PHLDA1, PHLDA2, and PHLDA3 as potential diagnostic biomarkers and therapeutic targets in HNSC. These genes are involved in critical pathways related to cancer progression and immune modulation. The findings suggest that targeting PHLDA genes may provide a novel approach for overcoming therapeutic resistance and improving patient outcomes in HNSC.</p>

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Upregulation of PHLDA genes drives malignancy and therapeutic resistance in head and neck Cancer

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Mostafa A. Abdel-Maksoud,
  • Abdulaziz Alamri,
  • Aljawharah Fahad,
  • Salman Alrokayan,
  • Mohammed Aufy,
  • Bushra Hafeez Kiani,
  • Hanyong Zhang,
  • Muhammad Mazhar Ayaz,
  • Yasir Hameed,
  • Saeedah Almutairi

摘要

Head and neck squamous cell carcinoma (HNSC) is a leading cause of morbidity and mortality worldwide. The roles of PHLDA genes in HNSC progression remain unclear. This study explores their expression, mutational landscape, and functional roles as potential diagnostic biomarkers and therapeutic targets. Eight HNSC cell lines and six normal oral keratinocyte cell lines were cultured, and RNA extraction and RT-qPCR analysis were conducted. The GSCA database validated gene expression in clinical HNSC samples. Methylation and survival analysis were performed using TCGA data, with survival correlation assessed via the KM Plotter tool and UALCAN database. Mutational analysis was done via cBioPortal, and immune-related correlations were analyzed using TISIDB. Functional assays were performed after siRNA-mediated knock down of PHLDA genes in SCC9 and SCC25 cells, including Western blot, CCK-8, colony formation, and wound healing assays. Our results demonstrate that PHLDA1, PHLDA2, and PHLDA3 are significantly upregulated in HNSC cell lines compared with normal controls, with PHLDA1 showing the most substantial increase. ROC analysis revealed that PHLDA1 exhibited the highest diagnostic potential for distinguishing HNSC from normal tissues. Methylation analysis showed hypomethylation of PHLDA genes in tumor tissues, particularly in the promoter regions. Higher expression of PHLDA genes correlated with poorer overall survival outcomes in HNSC patients. Mutational analysis revealed that PHLDA2 exhibited the highest mutation rate, with predominantly missense mutations. The PPI network analysis indicated that PHLDA genes interact with several cancer-related proteins, and DAVID analysis showed their involvement in processes like cell cycle regulation and tumorigenesis. Functional assays demonstrated that silencing of PHLDA genes in HNSC cells significantly impaired cell proliferation, clonogenic potential, and migration, suggesting their role as oncogenic regulators. Our study identifies PHLDA1, PHLDA2, and PHLDA3 as potential diagnostic biomarkers and therapeutic targets in HNSC. These genes are involved in critical pathways related to cancer progression and immune modulation. The findings suggest that targeting PHLDA genes may provide a novel approach for overcoming therapeutic resistance and improving patient outcomes in HNSC.