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The Role of PARP-1 and NF-κB in Bile-Induced DNA Damage and Oncogenic Profile in Hypopharyngeal Cells. | LitMetric

The Role of PARP-1 and NF-κB in Bile-Induced DNA Damage and Oncogenic Profile in Hypopharyngeal Cells.

Laryngoscope

The Yale Larynx Laboratory, Department of Surgery, Section of Otolaryngology, Yale School of Medicine, New Haven, Connecticut, USA.

Published: May 2023

AI Article Synopsis

  • The study investigates the connection between acidic bile reflux and hypopharyngeal squamous cell carcinoma, focusing on DNA damage and the roles of PARP-1 and NF-κB in cancer development.
  • Researchers hypothesized that PARP-1 activation correlates with DNA damage from acidic bile, which subsequently activates NF-κB and enhances oncogenic processes.
  • Results showed that while targeting NF-κB reduced DNA damage and improved cell survival, inhibiting PARP-1 resulted in persistent DNA damage and NF-κB activation, highlighting the early role of PARP-1 in bile reflux-related cancer.

Article Abstract

Objectives/hypothesis: We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process.

Study Design: In vitro study.

Methods: We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 μM Rucaparib (AG014699) and 10 μM BAY 11-7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs.

Results: We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype.

Conclusion: We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis.

Level Of Evidence: NA Laryngoscope, 133:1146-1155, 2023.

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Source
http://dx.doi.org/10.1002/lary.30284DOI Listing

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