Gasdermin D in Different Subcellular Locations Predicts Diverse Progression, Immune Microenvironment and Prognosis in Colorectal Cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Pyroptosis is a type of cell death that causes an immune reaction. Gasdermin D (GSDMD), as an executor of pyroptosis, has become an attractive target in cancer research. However, the clinical significance of GSDMD expression in different subcellular locations remains unclear.

Methods

GSDMD was detected by immunohistochemistry in 178 cases of colorectal cancer with follow-up information. General data and information on systemic inflammatory indicators were collected from case records, and the clinicopathological parameters were reviewed by microscopy. CD3 ⁺, CD4 ⁺, and CD8 ⁺ T lymphocytes, CD20 ⁺ B lymphocytes, and CD68 ⁺ macrophages were detected by immunohistochemistry. Univariate survival analysis (Kaplan–Meier method, Log rank test) and a multivariate Cox proportional hazard model were used to analyze the impact of GSDMD on overall survival.

Results

Survival analysis showed that high expression of cytoplasmic GSDMD was an independent favorable indicator for prognosis ( P=0.027) and improved the efficacy of chemotherapy ( P=0.012). Positive cytoplasmic GSDMD expression indicated lower probability of distant metastasis ( P=0.024), yet nuclear GSDMD expression predicted deeper infiltration depth ( P=0.007). Membranous GSDMD expression positively correlated with CD68 ⁺ macrophages in tumor center ( P=0.002) and CD8 ⁺ lymphocytes in tumor invasive front ( P=0.007). However, nuclear GSDMD was negatively related to CD68 ⁺ macrophages in tumor invasive front ( P<0.001) and CD8 ⁺ lymphocytes in tumor center ( P=0.069). Cytoplasmic GSDMD was associated with more CD3 ⁺ lymphocytes both in tumor center ( P=0.066) and tumor invasive front ( P=0.008). Moreover, positive membranous GSDMD indicated a lower neutrophil-to-lymphocyte ratio ( P=0.013).

Conclusion

GSDMD subcellular localization patterns are related to CRC progression and immune reaction, and should be investigated in future studies.

Related collections

Most cited references 33

Record: found
Abstract: found
Article: not found

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

0 comments Cited 41241 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Lorenzo Galluzzi, Ilio Vitale, Stuart A. Aaronson … (2018)

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

0 comments Cited 2336 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

Jianjin Shi, Yue Zhao, Kun Wang … (2015)

Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

0 comments Cited 2277 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Inflamm Res

Journal ID (iso-abbrev): J Inflamm Res

Journal ID (publisher-id): jir

Title: Journal of Inflammation Research

Publisher: Dove

ISSN (Electronic): 1178-7031

Publication date (Electronic): 25 November 2021

Publication date Collection: 2021

Volume: 14

Pages: 6223-6235

Affiliations

[1 ]Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China

[2 ]Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine , Hangzhou, Zhejiang, People’s Republic of China

[3 ]Department of Statistics, School of Mathematical Sciences, Anhui University , Hefei, Anhui, People’s Republic of China

[4 ]State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, People’s Republic of China

Author notes

Correspondence: Fangying Xu Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine , 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang, People’s Republic of China Tel +86—571-88208198 Fax +86-571-88208197 Email xfy@zju.edu.cn

Lichao Sun State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , 17 Panjiayuan South Lane, Beijing, 100021, People’s Republic of China Email sunlichao@cicams.ac.cn

[*]

These authors contributed equally to this work

Author information

Jiahui Wang http://orcid.org/0000-0001-7685-1715

Yixin Kang http://orcid.org/0000-0002-1131-6823

Fangying Xu http://orcid.org/0000-0001-6074-3234

Article

Publisher ID: 338584

DOI: 10.2147/JIR.S338584

PMC ID: 8630373

PubMed ID: 34858044

SO-VID: 852db73c-611c-45c9-a71c-7492596219c9

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 09 September 2021

Date accepted : 02 November 2021

Page count

Figures: 3, Tables: 9, References: 33, Pages: 13

Funding

Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;

Funded by: Open Projects of State Key Laboratory of Molecular Oncology;

Funded by: Program of Introducing Talents of Discipline to Universities;

This work was supported by the grants of National Natural Science Foundation of China under Grant 81772570; the Open Projects of State Key Laboratory of Molecular Oncology (SKLMO-KF2021-17) and Program of Introducing Talents of Discipline to Universities under Grant B13026.

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Cited by 10

See all cited by

Most referenced authors 957

See all reference authors

Gasdermin D in Different Subcellular Locations Predicts Diverse Progression, Immune Microenvironment and Prognosis in Colorectal Cancer

Read this article at

Abstract

Background

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 33

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 374

Cited by 10

Most referenced authors 957