Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Head and neck cancer (HNC) remains a significant global health challenge with suboptimal treatment outcomes.
• Existing therapies for HNC often result in considerable toxicity, necessitating the development of innovative treatment strategies.

Purpose of the Study:

• To identify and validate novel tumor-selective targets for enhancing HNC treatment.
• To investigate the role of Uroporphyrinogen decarboxylase (UROD) as a radiosensitizing target in HNC.

Main Methods:

• High-throughput RNA interference screening identified UROD as a potential radiosensitizing target.
• UROD knockdown was performed in HNC cell lines and in vivo models.
• Effects on apoptosis, cell cycle, tumor growth, iron homeostasis, and reactive oxygen species were analyzed.
• UROD expression in patient biopsies was assessed and correlated with clinical outcomes.

Main Results:

• UROD knockdown sensitized HNC cells to radiation, inducing apoptosis and cell cycle arrest.
• Reduced UROD expression suppressed tumor formation and delayed xenograft growth in mice.
• Radiosensitization was linked to altered iron homeostasis and increased oxidative stress.
• UROD was overexpressed in HNC tissues, and lower UROD mRNA levels correlated with better disease-free survival.
• UROD downregulation also sensitized other cancer types and enhanced chemotherapy efficacy.

Conclusions:

• Uroporphyrinogen decarboxylase (UROD) is a promising tumor-selective target for enhancing both radiation and chemotherapy in HNC.
• UROD modulation offers a potential strategy to improve clinical outcomes and predict radiation response in various human malignancies.