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PANoptosis subtypes predict prognosis and immune efficacy in gastric cancer

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Abstract

PANoptosis is a form of inflammatory programmed cell death that is regulated by the PANoptosome. This PANoptosis possesses key characteristics of pyroptosis, apoptosis, and necroptosis, yet cannot be fully explained by any of these cell death modes. The unique nature of this cell death mechanism has garnered significant interest. However, the specific role of PANoptosis-associated features in gastric cancer (GC) is still uncertain. Patients were categorized into different PAN subtypes based on the expression of genes related to the PANoptosome. We conducted a systematic analysis to investigate the variations in prognosis and tumor microenvironment (TME) among these subtypes. Furthermore, we developed a risk score, called PANoptosis-related risk score (PANS), which is constructed from genes associated with the PANoptosis. We comprehensively analyzed the correlation between PANS and GC prognosis, TME, immunotherapy efficacy and chemotherapeutic drug sensitivity. Additionally, we performed in vitro experiments to validate the impact of Keratin 7 (KRT7) on GC. We identified two PAN subtypes (PANcluster A and B). PANoptosome genes were highly expressed in PANcluster A. PANcluster A has the characteristics of favorable prognosis, abundant infiltration of anti-tumor lymphocytes, and sensitivity to immunotherapy, thus it was categorized as an immune-inflammatory type. Meanwhile, our constructed PANS can effectively predict the prognosis and immune efficacy of GC. Patients with low PANS have a good prognosis, and have the characteristics of high tumor mutation load (TMB), high microsatellite instability (MSI), low tumor purity and sensitivity to immunotherapy. In addition, PANS can also identify suitable populations for different chemotherapy drugs. Finally, we confirmed that KRT7 is highly expressed in GC. Knocking down the expression of KRT7 significantly weakens the proliferation and migration abilities of GC cells. The models based on PANoptosis signature help to identify the TME features of GC and can effectively predict the prognosis and immune efficacy of GC. Furthermore, the experimental verification results of KRT7 provide theoretical support for anti-tumor treatment.

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Data availability

The datasets analyzed during the current study are available at TCGA-STAD (GDC (cancer.gov)), GSE84437 (GEO Accession viewer (nih.gov)) and Supplementary Materials.

Abbreviations

PCD:

Programmed cell death

GC:

Gastric cancer

TME:

Tumor microenvironment

PANS:

PANoptosis-related risk score

KRT7 :

Keratin 7

TMB:

Tumor mutation burden

MSI:

Microsatellite instability

ICIs:

Immune checkpoint inhibitors

TCGA:

The cancer genome atlas

GEO:

Gene expression omnibus

GSVA:

Gene set variation analysis

ssGSEA:

Single-sample gene set enrichment analysis

ICPs:

Immune checkpoints

HLA:

Human leukocyte antigen

DEGs:

Differentially expressed genes

OS:

Overall survival time

TIDE:

Tumor immune dysfunction and exclusion

EDU:

5-Ethynyl-2′-deoxyuridine

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Acknowledgements

We would like to express our appreciation to TCGA-STAD (GDC (cancer.gov)) and GEO databases (https://www.ncbi.nlm.nih.gov/geo/) for providing the open-access databases utilized in this research study.

Funding

This research was funded by the Jiangxi Provincial Natural Science Foundation Key Project (20232ACB206032).

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Author notes

  1. Zitao Liu, Liang Sun and Xingyu Peng have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, 330006, Jiangxi, People’s Republic of China

    Zitao Liu, Liang Sun, Xingyu Peng, Jinfeng Zhu, Changlei Wu, Wenjie Zhu, Chao Huang & Zhengming Zhu

  2. Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China

    Jinfeng Zhu

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Contributions

ZTL, LS and XYP conceived and designed the study, while JFZ, CH and CLW collected data and clinical specimens. WJZ, ZTL and LS analyzed the data, conducted literature searches and assessed quality. ZMZ, ZTL and CH prepared and revised the first draft of the manuscript. All authors thoroughly reviewed the manuscript and agreed to the final version.

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Correspondence to Chao Huang or Zhengming Zhu.

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This study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University, and all patients signed informed consent.

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Liu, Z., Sun, L., Peng, X. et al. PANoptosis subtypes predict prognosis and immune efficacy in gastric cancer. Apoptosis 29, 799–815 (2024). https://doi.org/10.1007/s10495-023-01931-4

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