A novel defined pyroptosis-related gene signature for predicting the prognosis of
      ovarian cancer

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Abstract

Ovarian cancer (OC) is a highly malignant gynaecological tumour that has a very poor prognosis. Pyroptosis has been demonstrated in recent years to be an inflammatory form of programmed cell death. However, the expression of pyroptosis-related genes in OC and their correlations with prognosis remain unclear. In this study, we identified 31 pyroptosis regulators that were differentially expressed between OC and normal ovarian tissues. Based on these differentially expressed genes (DEGs), all OC cases could be divided into two subtypes. The prognostic value of each pyroptosis-related gene for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 7-gene signature was built and classified all OC patients in the TCGA cohort into a low- or high-risk group. OC patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group ( P < 0.001). Utilizing the median risk score from the TCGA cohort, OC patients from a Gene Expression Omnibus (GEO) cohort were divided into two risk subgroups, and the low-risk group had increased overall survival (OS) time ( P = 0.014). Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the OS of OC patients. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses indicated that immune-related genes were enriched and that the immune status was decreased in the high-risk group. In conclusion, pyroptosis-related genes play important roles in tumour immunity and can be used to predict the prognosis of OCs.

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

Yupeng Wang, Wenqing Gao, Xuyan Shi … (2017)

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Pore-forming activity and structural autoinhibition of the gasdermin family.

Jingjin Ding, Kun Wang, Wang-Wang Liu … (2016)

Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.

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Author and article information

Contributors

Hongbo Qi:

ORCID: http://orcid.org/0000-0003-3776-0487

qihongbocqmu@163.com

Journal

Journal ID (nlm-ta): Cell Death Discov

Journal ID (iso-abbrev): Cell Death Discov

Title: Cell Death Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2058-7716

Publication date (Electronic): 7 April 2021

Publication date PMC-release: 7 April 2021

Publication date Collection: 2021

Volume: 7

Electronic Location Identifier: 71

Affiliations

[1 ]GRID grid.452206.7, The Department of Obstetrics, , The First Affiliated Hospital of Chongqing Medical University, ; Chongqing, 400016 China

[2 ]GRID grid.203458.8, ISNI 0000 0000 8653 0555, State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, , Chongqing Medical University, ; Chongqing, 400016 China

[3 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, Guangzhou Women and Children’s Medical Center, , Guangzhou Medical University, ; Guangzhou 510623, Guangdong, China

Author information

Hongbo Qi http://orcid.org/0000-0003-3776-0487

Article

Publisher ID: 451

DOI: 10.1038/s41420-021-00451-x

PMC ID: 8026591

PubMed ID: 33828074

SO-VID: f38a6446-9006-4ca1-bb39-0eebb52ff334

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 5 January 2021

Date revision received : 25 February 2021

Date accepted : 9 March 2021

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81771613

Award ID: 81520108013

Award Recipient : Hongbo Qi

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Keywords: ovarian cancer,transcriptomics

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Keywords: ovarian cancer, transcriptomics

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A novel defined pyroptosis-related gene signature for predicting the prognosis of ovarian cancer

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Cancer statistics, 2019

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

Pore-forming activity and structural autoinhibition of the gasdermin family.

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