Multi-Omics Assessment of NQO1 Expression and Epigenetic Regulation in Cervical Cancer

Abstract

Background: Cervical cancer arises predominantly from persistent infection with high-risk HPV types and progresses through a well-defined sequence of CIN lesions. While current diagnostic strategies are effective, additional molecular indicators are needed to better characterize early transformation events. NQO1, a cytosolic flavoprotein involved in redox regulation, has been implicated in several solid tumors, yet its multi-layer behavior in cervical carcinogenesis remains insufficiently characterized. Methods: NQO1 mRNA expression, clinical stage association, and promoter methylation were assessed using TCGA-CESC RNA-seq and methylation datasets obtained via UALCAN. External transcriptomic validation was performed using GSE63514, comprising normal epithelium, CIN1–3, and invasive carcinoma. NQO1 protein expression was evaluated using Human Protein Atlas immunohistochemistry. Wilcoxon and Kruskal–Wallis tests were applied for TCGA analyses; ANOVA was used for lesion progression comparisons. Results: TCGA data demonstrated significantly elevated NQO1 expression in cervical tumors compared with normal cervix and showed consistently high levels across clinical stages. Promoter methylation analysis revealed tumor-specific hypomethylation at the NQO1 locus, suggesting epigenetic derepression. GSE63514 confirmed a progressive increase in NQO1 expression from normal epithelium through CIN grades to invasive cancer. Protein-level analysis showed strong cytoplasmic staining in tumor tissue, contrasting with weak or absent expression in normal epithelium. Survival patterns suggested a modest association between higher NQO1 expression and poorer outcomes. Discussion: The convergence of transcriptional overexpression, promoter hypomethylation, lesion-dependent activation, and protein-level upregulation positions NQO1 as a biologically meaningful marker of cervical epithelial transformation. Its early activation across CIN lesions indicates potential utility in molecular stratification. Conclusion: NQO1 demonstrates consistent multi-omics dysregulation in cervical cancer and may serve as an informative indicator of redox imbalance and lesion progression. Further mechanistic studies are warranted to clarify its functional role in HPV-associated carcinogenesis.

Keywords

• Cervical cancer
• NQO1
• HPV-driven carcinogenesis
• Multi-omics analysis
• Epigenetic deregulatio
• Promoter hypomethylation
• Gene expression profiling
• Biomarker discovery
• Redox metabolism

Servikal Kanserde NQO1 Ekspresyonu ve Epigenetik Düzenlenmesinin Çoklu-Omik Değerlendirmesi

Abstract

Servikal kanser, HPV enfeksiyonunun neden olduğu biyolojik streslerin birikimiyle gelişen çok aşamalı bir malignitedir. Bu çalışma, NQO1’in servikal kanser biyolojisindeki rolünü aydınlatmak amacıyla transkriptomik, epigenetik, lezyon-progresyonu ve protein düzeylerini kapsayan çoklu-omik bir değerlendirme sunmaktadır. TCGA-CESC verileri, NQO1’in primer servikal tümörlerde normal dokuya kıyasla belirgin şekilde yüksek seviyelerde eksprese edildiğini ve bu artışın klinik evreler boyunca stabil şekilde korunduğunu göstermiştir. Promoter bölgesinde gözlenen hipometilasyon, NQO1 aktivasyonunun epigenetik olarak derepresyona uğramış olabileceğini düşündürmektedir. GSE63514 kohortunda normal epitelden CIN1–CIN3’e ve invaziv kansere doğru kademeli bir NQO1 artışı gözlenmiş olup bu bulgu, lezyon şiddeti ile NQO1 aktivasyonu arasındaki biyolojik uyumu desteklemektedir. Human Protein Atlas verileri, tümör dokusunda yoğun sitoplazmik NQO1 pozitifliğini doğrulamıştır. Sağkalım analizleri, yüksek NQO1 ekspresyonunun daha kötü klinik sonuçlarla ilişkili olabileceğini göstermiştir. Bulgular, NQO1’in servikal kanser gelişiminde erken ve sürekli aktif bir moleküler bileşen olduğunu ortaya koymakta ve tanısal, prognostik ve potansiyel terapötik değerini desteklemektedir.

Keywords

• servikal kanser
• NQO1
• epigenetik düzenlem
• promoter hipometilasyon
• çoklu-omik anali
• HPV
• CIN progresyonu
• biyobelirteç

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