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High pyroptosis activity in pancreatic adenocarcinoma: poor prognosis and oxaliplatin resistance

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Abstract

Background

Pyroptosis, as a type of inflammatory programmed cell death, has been studied in inflammatory diseases and numerous cancers but its role in pancreatic ductal adenocarcinoma (PDAC) remains further exploration.

Methods

A TCGA-PDAC cohort was enrolled for bioinformatics analysis to investigate the effect of pyroptosis on the prognosis and drug sensitivity of patients. PA-TU-8988T and CFPAC-1 cells were selected for investigating the role of GSDMC in PDAC.

Results

A distinct classification pattern of PDAC mediated by 21 pyroptosis-related genes (PRGs) was identified. It was suggested that higher pyroptosis activity was associated with poor prognosis of patients and higher tumor proliferation rates. We further established a prognostic model based on three PRGs (GSDMC, CASP4 and NLRP1) and the TCGA-PDAC cohort was classified into low and high-risk subgroups. It is noteworthy that the high-risk group showed significantly higher tumor proliferation rates and was proved to be highly correlated with oxaliplatin resistance. Further experiments suggested that overexpression of GSDMC promoted the proliferation and oxaliplatin resistance of PA-TU-8988T cells in vitro and vivo, while downregulation of GSDMC showed opposite effects in CFPAC-1 cells. Finally, we found that the activation of pentose phosphate pathway (PPP) was the mechanism by which GSDMC overexpression promoted the proliferation and oxaliplatin resistance of pancreatic cancer cells.

Conclusions

In this study, we found that higher pyroptosis activity is associated with worse prognosis and oxaliplatin resistance of PDAC patients. In addition, as a core effector of pyroptosis, GSDMC promoted proliferation and oxaliplatin resistance of pancreatic cancer cells, which will provide new therapeutic target for PDAC patients.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Not applicable.

Funding

This work was supported by the grant from the National Natural Science Foundation of China (82173206, 82272974), Natural Science Foundation of Jiangsu Province (BK20221416), Construction Program of Jiangsu Provincial Clinical Research Center Support System (BL2014084), the Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Outstanding Talent (to YM, JCRCA2016009), Clinical Science and Technology Climbing program - “Spark” basic research project (ZJ202124). All samples used in current study were obtained from Pancreas Biobank, The First Affiliated Hospital with Nanjing Medical University, which is a part of Jiangsu Biobank of Clinical Resource.

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Author notes

  1. Guangfu Wang, Jin Chen and Shangnan Dai have contributed equally to this work.

Authors and Affiliations

  1. Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Guangfu Wang, Shangnan Dai, Jinfan Zhang, Yong Gao, Lingdi Yin, Kuirong Jiang, Yi Miao & Zipeng Lu

  2. Pancreas Institute, Nanjing Medical University, Nanjing, China

    Guangfu Wang, Shangnan Dai, Jinfan Zhang, Yong Gao, Lingdi Yin, Kuirong Jiang, Yi Miao & Zipeng Lu

  3. Pancreas Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China

    Yi Miao

  4. Department of Gynecological Oncology, Jiangsu Cancer Hospital, Nanjing, China

    Jin Chen

Authors
  1. Guangfu Wang
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Contributions

Guangfu Wang designed and drafted the manuscript. Shangnan Dai and Jin Chen conducted the analysis. Yong Gao, Lingdi Yin and Jinfan Zhang conducted the literature search. Kuirong Jiang, Yi Miao and Zipeng Lu designed, led, supervised the study, and critically revised the manuscript. All authors approved the final draft submitted, read and agreed to the published version of the manuscript.

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Correspondence to Yi Miao or Zipeng Lu.

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Wang, G., Chen, J., Dai, S. et al. High pyroptosis activity in pancreatic adenocarcinoma: poor prognosis and oxaliplatin resistance. Apoptosis 29, 344–356 (2024). https://doi.org/10.1007/s10495-023-01901-w

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