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Cancer Cell International
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Colorectal Cancer | Primary research

A pan-cancer analysis of molecular characteristics and oncogenic role of gasdermins

Authors: Mingchao Mu, Qiaoling Yu, Qin Zhang, Jing Guo, Xingjie Wang, Xuejun Sun, Junhui Yu

Published in: Cancer Cell International | Issue 1/2022

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Abstract

Background

The gasdermins (GSDMs) family is proposed to be pore-forming effector proteins that cause cell membrane permeabilization and pyroptosis. Despite our increasing knowledge of GSDMD, GSDME and GSDMB, the biological functions and the regulation of GSDM expression and activation remain elusive for most GSDMs. In this study, we analyzed the molecular characteristics and oncogenic role of GSDM family genes systematically.

Methods

TCGA, CCLE, cBioPortal, GEPIA, CellMiner and BioGRID databases were utilized in this study. Immunohistochemical analysis and a series of in vitro experiments were conducted.

Results

We found that, in cancer, GSDM genes and their expressions extensively changed, which were associated with patient survival. The expression of GSDMs was widely associated with cancer-related pathways, drug resistance, immune subtypes, tumor microenvironment and cancer cell stemness. However, an intra- and inter-cancer heterogeneity was discovered regarding the corresponding GSDM gene. We found that GSDMA and GSDMB regulated drug resistance to the opposite direction of GSDME. In colorectal cancer, GSDME might be a positive regulator in cell invasion and metastasis through cell migration and angiogenesis, while GSDMA, GSDMB and GSDMD might be a negatively regulator of cell migration.

Conclusions

GSDM family genes might play important roles in cancer other than pyroptosis. We suggest more efforts be made to investigate the GSDM family and each GSDM gene be studied as an entity in each type of cancer.
Appendix
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Literature
1.
Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20(3):143–57.PubMedCrossRef
2.
Saeki N, Kuwahara Y, Sasaki H, Satoh H, Shiroishi T. Gasdermin (Gsdm) localizing to mouse Chromosome 11 is predominantly expressed in upper gastrointestinal tract but significantly suppressed in human gastric cancer cells. Mamm Genome. 2000;11(9):718–24.PubMedCrossRef
3.
Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X, et al. Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis. Cell. 2020;180(5):941–55.PubMedCrossRef
4.
Kuang S, Zheng J, Yang H, Li S, Duan S, Shen Y, et al. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc Natl Acad Sci. 2017;114(40):10642–7.PubMedPubMedCentralCrossRef
5.
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526(7575):660–5.PubMedCrossRef
6.
Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547(7661):99–103.PubMedCrossRef
7.
Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun. 2017;8(1):1–14.CrossRef
8.
Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535(7610):111–6.PubMedCrossRef
9.
Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–71.PubMedCrossRef
10.
Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579(7799):415–20.PubMedPubMedCentralCrossRef
11.
Liu Y, Fang Y, Chen X, Wang Z, Liang X, Zhang T, et al. Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci Immunol. 2020;5(43):eaax7969.PubMedCrossRef
12.
13.
Hu B, Jin J, Guo A-Y, Zhang H, Luo J, Gao G. GSDS 2.0: an upgraded gene feature visualization server. Bioinformatics. 2015;31(8):1296–7.PubMedCrossRef
14.
15.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.PubMedCrossRef
16.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.PubMedPubMedCentralCrossRef
17.
Liu C-J, Hu F-F, Xia M-X, Han L, Zhang Q, Guo A-Y. GSCALite: a web server for gene set cancer analysis. Bioinformatics. 2018;34(21):3771–2.PubMedCrossRef
18.
Shankavaram UT, Varma S, Kane D, Sunshine M, Chary KK, Reinhold WC, et al. Cell Miner: a relational database and query tool for the NCI-60 cancer cell lines. BMC Genomics. 2009;10:277.PubMedPubMedCentralCrossRef
19.
20.
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4(1):1–11.CrossRef
21.
22.
23.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98-w102.PubMedPubMedCentralCrossRef
24.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005;102(43):15545–50.PubMedPubMedCentralCrossRef
25.
Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267–73.PubMedCrossRef
26.
Lv XH, Liu BQ, Li XM, Wang XC, Li XL, Ahmed N, et al. Integrin α4 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in human colon cancer. Anat Rec. 2016;299(6):741–7.CrossRef
27.
Panganiban RA, Sun M, Dahlin A, Park H-R, Kan M, Himes BE, et al. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol. 2018;142(5):1469–78.PubMedPubMedCentralCrossRef
28.
Schwander M, Sczaniecka A, Grillet N, Bailey JS, Avenarius M, Najmabadi H, et al. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function. J Neurosci. 2007;27(9):2163–75.PubMedPubMedCentralCrossRef
29.
Van Laer L, Vrijens K, Thys S, Van Tendeloo V, Smith R, Van Bockstaele D, et al. DFNA5: hearing impairment exon instead of hearing impairment gene? J Med Genet. 2004;41(6):401–6.PubMedPubMedCentralCrossRef
30.
Camp GV, Coucke P, Balemans W, Van Velzen D, Van de Bilt C, Van Laer L, et al. Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15. Hum Mol Genet. 1995;4(11):2159–63.PubMedCrossRef
31.
He W, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015;25(12):1285–98.PubMedPubMedCentralCrossRef
32.
33.
Saeki N, Kim D, Usui T, Aoyagi K, Tatsuta T, Aoki K, et al. GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-β-dependent apoptotic signalling. Oncogene. 2007;26(45):6488–98.PubMedCrossRef
34.
Wang WJ, Chen D, Jiang MZ, Xu B, Li XW, Chu Y, et al. Downregulation of gasdermin D promotes gastric cancer proliferation by regulating cell cycle-related proteins. J Dig Dis. 2018;19(2):74–83.PubMedCrossRef
35.
Shen X, Zhang Q, He Z, Xiao S, Li H, Huang Z. Overexpression of gasdermin D promotes invasion of adenoid cystic carcinoma. Int J Clin Exp Pathol. 2020;13(7):1802.PubMedPubMedCentral
36.
Komiyama H, Aoki A, Tanaka S, Maekawa H, Kato Y, Wada R, et al. Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB). Genes Genet Syst. 2010;85(1):75–83.PubMedCrossRef
37.
Tamura M, Tanaka S, Fujii T, Aoki A, Komiyama H, Ezawa K, et al. Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Genomics. 2007;89(5):618–29.PubMedCrossRef
38.
Treviño ENG, González PD, Salgado CIV, Garza AM. Effects of pericytes and colon cancer stem cells in the tumor microenvironment. Cancer Cell Int. 2019;19(1):1–12.
39.
Jahanafrooz Z, Mosafer J, Akbari M, Hashemzaei M, Mokhtarzadeh A, Baradaran B. Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment. J Cell Physiol. 2020;235(5):4153–66.PubMedCrossRef
40.
Tauriello DV, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554(7693):538–43.PubMedCrossRef
41.
Ren B, Cui M, Yang G, Wang H, Feng M, You L, et al. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer. 2018;17(1):1–15.CrossRef
42.
43.
Fan JX, Deng RH, Wang H, Liu XH, Wang XN, Qin R, et al. Epigenetics-based tumor cells pyroptosis for enhancing the immunological effect of chemotherapeutic nanocarriers. Nano Lett. 2019;19(11):8049–58.PubMedCrossRef
Metadata
Title
A pan-cancer analysis of molecular characteristics and oncogenic role of gasdermins
Authors
Mingchao Mu
Qiaoling Yu
Qin Zhang
Jing Guo
Xingjie Wang
Xuejun Sun
Junhui Yu
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02483-4

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