Human papillomavirus-driven repression of NRF2 signalling confers chemo-radio sensitivity and predicts prognosis in head and neck squamous cell carcinoma

Ramesh, P.; Bovilla, Venugopal R.; Manoli, Nandini; Dasegowda, Krishnappa B.; Siddegowda, Siddegowda M.; Chandrashekarappa, Shilpa; Somasundara, Vishveshwara M.; Prasada, K. Shyama; Ramasamy, Rajesh; Devegowda, Devananda; Thimmulappa, Rajesh K.

doi:10.1016/j.freeradbiomed.2023.06.011

Cited by 7 publications

(3 citation statements)

References 37 publications

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“… 42 A recent study reported that ectopic expression of HPV-E6/E7 plasmid in various cancer cells repressed constitutive Nrf2 activity. 43 In this study, Nrf2 and HO-1 were highly expressed in ferroptotic HeLa cells, suggesting that the Nrf2/HO-1 pathway may be a key mechanism by which erastin regulates ferroptosis. Further analysis using the siRNA technique demonstrated that HO-1 knockdown significantly diminished the erastin activity on colony formation, migration, invasion, and ROS production of HeLa cells.…”

Section: Discussionmentioning

confidence: 51%

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway

Wei,

Huang,

Huang

et al. 2023

Int J Immunopathol Pharmacol

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Objective Our research aims to assess the influence of erastin, a ferroptosis-inducing agent, on cervical cancer cells. Introduction Cervical cancer is a prevalent malignancy in females. Dysregulation of ferroptosis, a form of cell demise reliant on iron, is implicated in several cancers. Methods The effect of erastin on HeLa and SiHa was detected by transwell assay, scratch test, and colony formation assay, while cell apoptosis was detected using flow cytometry. Cellular reactive oxygen species (ROS) generation was detected using the dichloro-dihydro-fluorescein diacetate assay. Sequencing analysis identified differentially expressed genes (DEGs), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment analyses were employed to identify the target gene. Subsequently, the utilization of small interfering RNA (siRNA) was employed to suppress the targeted gene expression in HeLa cells, thereby effectively mitigating the impact of erastin on various cellular processes including invasion, colony formation, migration, and ROS generation. Results The findings indicate that erastin attenuates the viability of both HeLa cells (IC50 = 30.88 µM) and SiHa cells (IC50 = 29.40 µM). Treatment with erastin at 10 µM inhibits the invasion, colony formation, and migration of both HeLa and SiHa cells within 24 h. Ferrostatin-1 (1 µM) notably alleviates the inhibitory effects of erastin of HeLa and SiHa cells. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target, heme oxygenase-1 (HO-1), was found in erastin-treated cells compared to the control group. When knocked down HO-1 in HeLa cells, effectively counteracting the effects of erastin on the invasion, colony formation, migration, and ROS production in HeLa cells. Conclusion Our research demonstrates that erastin induces ferroptosis and the accumulation of ROS in cervical cancer cells by activating the Nrf2/HO-1 pathway, significantly reducing cell proliferation and motility. These findings propose a potential molecular mechanism of erastin-mediated cervical cancer development.

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Section: Discussionmentioning

confidence: 51%

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway

Wei,

Huang,

Huang

et al. 2023

Int J Immunopathol Pharmacol

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“…By the mean expression value, patients were classified into the upper and lower quartiles and correlated with OS. Low expression of NRF2, TP53 and NQO1 genes and high expression of the KEAP1 gene were significantly associated with better survival of patients with HPV-positive HNSCC [47].…”

Section: Mrnasmentioning

confidence: 93%

Potential Transcript-Based Biomarkers Predicting Clinical Outcomes of HPV-Positive Head and Neck Squamous Cell Carcinoma Patients

Muñoz-Bello,

Romero-Córdoba,

García-Chávez

et al. 2024

Cells

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Human papillomavirus (HPV)-positive Head and Neck Squamous Cell Carcinomas (HNSCC) comprise a particular cancer entity traditionally associated with better clinical outcomes. Around 25% of HNSCC are HPV positive, HPV16 being the most prevalent type. Nevertheless, close to 30% of the HPV-positive patients have an unfavorable prognosis, revealing that this type of tumor exhibits great heterogeneity leading to different clinical behaviors. Efforts have been made to identify RNA molecules with prognostic value associated with the clinical outcome of patients with HPV-positive HNSCC, with the aim of identifying patients at high risk of metastasis, disease recurrence, and poor survival, who would require closer clinical follow-up and timely intervention. Moreover, the molecular identification of those HPV-positive HNSCC patients with good prognosis will allow the implementation of de-escalating therapeutic strategies, aiming to reduce side effects, resulting in a better quality of life. This review compiles a series of recent studies addressing different methodological and conceptual approaches aimed at searching for potential gene expression-based biomarkers associated with the prognosis of patients with HPV-positive HNSCC.

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“… 5 These proteins, by jointly regulating CDK4 and p53, 6 supervise the transition from the G1 phase to the S phase. 7 Mutations or deletions within this gene have been linked to numerous cancers, establishing its significance as a critical oncogene. Recent literature 8 , 9 , 10 indicates that while apoptosis induction remains a common chemotherapeutic action mechanism, primary apoptosis regulators, notably p53 and p16/CDKN2A, are often inactivated within tumour tissues, which can lead to resistance against such treatments.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of CDKN2A in head and neck squamous cell carcinoma via pathomics and machine learning

Wang,

Zhou,

et al. 2024

J Cellular Molecular Medi

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This study aims to enhance the prognosis prediction of Head and Neck Squamous Cell Carcinoma (HNSCC) by employing artificial intelligence (AI) to analyse CDKN2A gene expression from pathology images, directly correlating with patient outcomes. Our approach introduces a novel AI‐driven pathomics framework, delineating a more precise relationship between CDKN2A expression and survival rates compared to previous studies. Utilizing 475 HNSCC cases from the TCGA database, we stratified patients into high‐risk and low‐risk groups based on CDKN2A expression thresholds. Through pathomics analysis of 271 cases with available slides, we extracted 465 distinctive features to construct a Gradient Boosting Machine (GBM) model. This model was then employed to compute Pathomics scores (PS), predicting CDKN2A expression levels with validation for accuracy and pathway association analysis. Our study demonstrates a significant correlation between higher CDKN2A expression and improved median overall survival (66.73 months for high expression vs. 42.97 months for low expression, p = 0.013), establishing CDKN2A's prognostic value. The pathomic model exhibited exceptional predictive accuracy (training AUC: 0.806; validation AUC: 0.710) and identified a strong link between higher Pathomics scores and cell cycle activation pathways. Validation through tissue microarray corroborated the predictive capacity of our model. Confirming CDKN2A as a crucial prognostic marker in HNSCC, this study advances the existing literature by implementing an AI‐driven pathomics analysis for gene expression evaluation. This innovative methodology offers a cost‐efficient and non‐invasive alternative to traditional diagnostic procedures, potentially revolutionizing personalized medicine in oncology.

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Human papillomavirus-driven repression of NRF2 signalling confers chemo-radio sensitivity and predicts prognosis in head and neck squamous cell carcinoma

Cited by 7 publications

References 37 publications

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway

Potential Transcript-Based Biomarkers Predicting Clinical Outcomes of HPV-Positive Head and Neck Squamous Cell Carcinoma Patients

Prognostic value of CDKN2A in head and neck squamous cell carcinoma via pathomics and machine learning

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