Prognostic and chemotherapeutic implications of a novel four-gene pyroptosis model in head and neck squamous cell carcinoma

PeerJ. 2024 May 13:12:e17296. doi: 10.7717/peerj.17296. eCollection 2024.

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers. Chemotherapy remains one dominant therapeutic strategy, while a substantial proportion of patients may develop chemotherapeutic resistance; therefore, it is particularly significant to identify the patients who could achieve maximum benefits from chemotherapy. Presently, four pyroptosis genes are reported to correlate with the chemotherapeutic response or prognosis of HNSCC, while no study has assessed the combinatorial predicting efficacy of these four genes. Hence, this study aims to evaluate the predictive value of a multi-gene pyroptosis model regarding the prognosis and chemotherapeutic responsiveness in HNSCC.

Methods: By utilizing RNA-sequencing data from The Cancer Genome Atlas database and the Gene Expression Omnibus database, the pyroptosis-related gene score (PRGscore) was computed for each HNSCC sample by performing a Gene Set Variation Analysis (GSVA) based on four genes (Caspase-1, Caspase-3, Gasdermin D, Gasdermin E). The prognostic significance of the PRGscore was assessed through Cox regression and Kaplan-Meier survival analyses. Additionally, chemotherapy sensitivity stratified by high and low PRGscore was examined to determine the potential association between pyroptosis activity and chemosensitivity. Furthermore, chemotherapy sensitivity assays were conducted in HNSCC cell lines in vitro.

Results: As a result, our study successfully formulated a PRGscore reflective of pyroptotic activity in HNSCC. Higher PRGscore correlates with worse prognosis. However, patients with higher PRGscore were remarkably more responsive to chemotherapy. In agreement, chemotherapy sensitivity tests on HNSCC cell lines indicated a positive association between overall pyroptosis levels and chemosensitivity to cisplatin and 5-fluorouracil; in addition, patients with higher PRGscore may benefit from the immunotherapy. Overall, our study suggests that HNSCC patients with higher PRGscore, though may have a less favorable prognosis, chemotherapy and immunotherapy may exhibit better benefits in this population.

Keywords: Chemotherapy sensitivity; Head and neck squamous cell carcinoma; Prognosis; Pyroptosis-related gene score.

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use
  • Gasdermins
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / genetics
  • Head and Neck Neoplasms* / pathology
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism
  • Prognosis
  • Pyroptosis* / drug effects
  • Pyroptosis* / genetics
  • Squamous Cell Carcinoma of Head and Neck* / drug therapy
  • Squamous Cell Carcinoma of Head and Neck* / genetics
  • Squamous Cell Carcinoma of Head and Neck* / mortality
  • Squamous Cell Carcinoma of Head and Neck* / pathology

Substances

  • GSDME protein, human
  • GSDMD protein, human
  • CASP3 protein, human

Grants and funding

This work is supported by the National Natural Science Foundation of China (82272899, 81902782, 82203180, 51733005, and 52173287), the Research Funding from West China School/Hospital of Stomatology Sichuan University (No.RCDWJS2022-16), the Postdoctoral Research Funding of Sichuan University (2022SCU12132), the Research and Develop Program of West China Hospital of Stomatology of Sichuan University (No. RD-02-202204), the Key Research Program of Sichuan Provincial Science and Technology Agency (2023YFS0127), the Clinical and Translational Medicine Research Foundation of Chinese Academy of Medical Sciences (2022-I2M-C&T-B-111), and the Research and Develop Program, West China Hospital of Stomatology Sichuan University (RD-03-202307). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.