An analysis of gasdermin family of genes in UCEC with respect to malignancy status, mutation percentages and histologic diagnosis_Latest Articles_国际期刊

An analysis of gasdermin family of genes in UCEC with respect to malignancy status, mutation percentages and histologic diagnosis

来源：发布时间：2024-11-21 16:16:02 浏览次数：次【字体：小大】

Original Research Paper

Published: 06 May 2024

Caglar Berkel

Volume 5, pages 105–115, (2024)

Abstract

Pyroptosis is a type of programmed lytic cell death mechanism associated with the activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (GSDMA-E and PJVK), resulting in the formation of pores in cellular membranes such as plasma membrane and mitochondrial membranes. Here, I show that GSDMC expression was increased, GSDME (DFNA5) and PJVK (DFNB59) expression were decreased in uterine corpus endometrial carcinoma (UCEC) cells compared to normal non-malignant endometrial cells. Total percentage of patients affected by mutations in gasdermin family of genes was the highest in UCEC compared to other cancer types. The highest mutation percentage in UCEC patients among the members of the protein family was observed for GSDME which also showed the most significant difference in the mRNA expression among other family members between tumor and normal samples, possibly pointing to its relatively higher importance in the pathogenesis of UCEC. Gasdermin family of genes (except GSDMA) had higher transcript levels in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma, demonstrating the histotype-dependent expression of the most of gasdermin family of genes in UCEC. Transcript levels of certain gasdermin family members also differed based on residual tumor status and histologic tumor grade; however, the expression of any gasdermin genes did not change depending on menopause status. This study suggests that a better mechanistic understanding of pyroptotic cell death in uterine corpus endometrial carcinoma might help identify novel therapeutic targets for the management of this gynecological malignancy.

Introduction

Uterine corpus endometrial carcinoma (UCEC) is the second most common gynecological malignancy with high mortality rates. This malignancy has two pathological types: estrogen-dependent endometrioid adenocarcinomas and estrogen-independent serous adenocarcinomas (Huang et al., 2022; Liu & Jing, 2022; Liu et al., 2022; Zhang & Yang, 2021; Zhang et al., 2023). Endometrial carcinoma has also been classified into two main clinicopathological and molecular types: type I is the endometrioid adenocarcinoma (80–90% of all cases), and type II comprises non-endometrioid subtypes including serous, clear cell and undifferentiated carcinomas, as well as carcinosarcoma/malignant-mixed Müllerian tumour (10–20%) (ACOG, 2006; Colombo et al., 2016).

Pyroptosis is a type of lytic pro-inflammatory cell death mechanism induced following the activation of inflammatory caspases (such as caspase-1) by inflammasome complexes including NLRP3 inflammasome. Pyroptotic cell death is mediated by gasdermin (GSDM) proteins (Berkel & Cacan, 2021, 2023; Broz et al., 2020; Liu et al., 2021; Rühl & Broz, 2022; Wei et al., 2022). Gasdermin protein family have six members in humans: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and PJVK (DFNB59). These proteins are classified as pore-forming effector molecules which induce pyroptosis by disrupting the integrity of the cellular membranes (such as plasma membrane, mitochondrial membranes) upon their activation (Broz et al., 2020; Liu et al., 2021; Miao et al., 2023; Rühl & Broz, 2022). Mechanistically, pyroptosis involves the cleavage of central linker regions (between N- and C-terminal domains) of GSDM proteins by certain caspases, and the release of the GSDM N-terminal (NT) fragment, which targets, for instance, the plasma membrane to form large β-barrel pores of ~ 18 nm in size (this pore formation activity has been verified for all members of the family with the exception of PJVK). These pores formed following the oligomerization of NT gasdermin domains then allow the release of certain pro-inflammatory cytokines such as IL-1β and IL-18 in addition to other cytosolic proteins (cellular alarmins, including ATP, cleaved GSDMs and other cytokines and chemokines) into the extracellular environment (Berkel & Cacan, 2023; Broz et al., 2020; Liu et al., 2021; Rühl & Broz, 2022; Wei et al., 2022). The release of larger molecules such as LDH and HMGB1 also requires the NINJ1-mediated plasma membrane rupture following the formation of gasdermin pores (Berkel & Cacan, 2023; Degen et al., 2023; Kayagaki et al., 2021; Lee et al., 2024; Ramos et al., 2024).

Here, I showed that GSDMC expression is increased, GSDME and PJVK expression are decreased in uterine corpus endometrial carcinoma (UCEC) cells compared to normal endometrial cells. Total percentage of cases affected by mutations in genes encoding gasdermin family of proteins was found to be the highest in UCEC among other cancer types. I also showed that gasdermin family of genes have higher transcript levels in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma, except for GSDMA. This points to the presence of histological type-dependent expression of the most members of the family in patients with UCEC. Besides, I reported that certain members of the family have differential expression based on residual tumor status and histologic tumor grade. Lastly, I found that the expression of the gasdermin family members in UCEC is independent of menopausal status. Although some previous studies have pointed to the involvement of pyroptotic cell death in patients with UCEC by mostly developing prediction models (Huang et al., 2022; Liu & Jing, 2022; Liu et al., 2022; Zhang & Yang, 2021; Zhang et al., 2023), I here provided novel insights in the context of pyroptotic cell death in uterine corpus endometrial carcinoma. This study suggests that a better mechanistic understanding of pyroptosis in UCEC might help identify novel therapeutic targets for the management of this gynecological malignancy.

Results

GSDMC expression is increased, GSDME and PJVK expression are decreased in uterine corpus endometrial carcinoma compared to normal endometrial cells

First, I compared mRNA levels of gasdermin family of genes (GSDMA-E and PJVK) between tumor samples from patients with uterine corpus endometrial carcinoma (UCEC) and normal control samples from healthy individuals. I found that the expression of GSDMC is increased (p value = 2.2e−08); however, the expression of GSDME and PJVK (Pejvakin) is decreased in tumor samples compared to normal samples (Fig. 1, p values < 2e−16 and = 9.3e−09, respectively). The expression of GSDMA, GSDMB and GSDMD did not significantly differ between tumor and normal samples in the context of UCEC (Fig. 1, p values = 0.65, 0.05 and 0.97, respectively).

Total percentage of cases affected by mutations in genes encoding gasdermin family of proteins is the highest in uterine corpus endometrial carcinoma (UCEC) among other cancer types

Later, I identified top 5 cancer types for which the percentage of cases affected by mutations in genes encoding gasdermin family of proteins is the highest, for each 6 genes, separately (GSDMA-E and PJVK) (Fig. 2). I found that the percentage of patients affected by mutations in GSDMD, GSDME (DFNA5) or PJVK (DFNB59) is the highest in uterine corpus endometrial carcinoma (UCEC) compared to other cancer types (Fig. 2, last 3 plots). For GSDMA, GSDMB and GSDMC, the percentage of cases affected by mutations in these genes was the second highest in UCEC, following SKCM (skin cutaneous melanoma), among other cancer types (Fig. 2, first 3 plots). When the percentage of cases affected by mutations in these 6 gasdermin genes for the top 5 cancer types (for each gene) were added (given in Fig. 2), UCEC had the highest sum of mutation percentages (24.22%) in gasdermin family of genes, followed by SKCM (20.01%) and CHOL (Cholangiocarcinoma, 5.88%) (Table 1).

Table 1 Sum of mutation percentages of gasdermin family of genes in different cancer types

Gasdermin family of genes have higher transcript levels in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma, except for GSDMA

Later, I showed that the expression of gasdermin family of genes does not depend on tumor status (defined as the condition or state of the tumor at a particular time; “tumor free” vs “with tumor”) (Fig. 3). However, based on histologic diagnosis (i.e. diagnosis of tumor based on the type of tissue, where type is determined based on the microscopic examination of tissue), I found that, for all gasdermin genes except GSDMA, transcript levels are higher in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma (p values (endometrioid vs serous) are 0.13, 7e−11, 8.5e−06, 0.0016, 2.3e−09 and 0.0089, respectively for GSDMA-E and PJVK) (Fig. 4). In plots, “Mixed” represent mixed serous and endometrioid endometrial adenocarcinoma (Fig. 4). For GSDMB and GSDME, mixed histological type had higher expression than endometrioid histological type of UCEC (Fig. 4; p values are 0.03 and 0.028, respectively).

Analysis of mRNA expression of gasdermin family of genes based on residual tumor status

Next, I studied the expression of these 6 genes in terms of residual tumor status in uterine corpus endometrial carcinoma (UCEC) samples. Here, R0 is defined as “no residual tumor”, R1 is defined as “microscopic residual tumor (no gross residual disease but positive microscopic margins)”, R2 is defined as “macroscopic residual tumor (grossly visible residual disease)”, and RX is defined as “presence of residual tumor cannot be assessed (the presence of residual tumor or margin status cannot be assessed)”. I found that, for GSDMC and GSDME, R2 samples have higher expression than R1 samples (Fig. 5, p values are 0.023 and 0.035, respectively). GSDMC expression was also higher in R2 samples compared to R0 samples (Fig. 5, p = 0.011) and to R1 samples (Fig. 5). GSDMA and GSDMB transcript levels were found to not change depending on residual tumor status (Fig. 5).

Analysis of the expression of gasdermin family of genes based on histologic tumor grade

Then, I analyzed how the transcript levels of genes encoding gasdermin family of proteins differ depending on the histologic tumor grade in uterine corpus endometrial carcinoma. Firstly, I found that the expression of GSDMC and GSDMD shows an increasing trend from grade 1 (G1) to high grade (G4) (Fig. 6). Here, grade 1 (G1) represents well differentiated (low grade) tumors, grade 2 (G2) represents moderately differentiated (intermediate grade) tumors, grade 3 (G3) represents poorly differentiated (high grade) tumors, and grade 4 (G4) represents undifferentiated (high grade) tumors. For GSDMB, G3 tumors had higher expression than G2 tumors (Fig. 6, p value = 0.039). For GSDMC, G3 tumors had higher expression than G1 tumors. For GSDMD, G3 tumors had increased expression than both G1 and G2 tumors. Similarly, for GSDME, G3 tumors had higher expression than both G1 and G2 tumors (Fig. 6, p values are 0.0011 and 1e−06, respectively). The expression of GSDMA and PJVK did not differ depending on histologic tumor grade (Fig. 6). Lastly, I showed that mRNA expression of genes encoding gasdermin family of proteins does not differ based on menopause status (pre-menopausal vs post-menopausal) (Fig. 7).

Discussion

Uterine corpus endometrial carcinoma (UCEC) is one of the most prevalent and lethal gynecologic malignances. Its incidence and mortality rates of patients with UCEC are increasing annually, while its age of onset is decreasing (Sung et al., 2021). Pyroptosis and pore-forming proteins functioning in this cell death mechanism have not been studied in detail in this malignancy; although some risk prediction models have been previously constructed based on pyroptosis-associated genes (Huang et al., 2022; Liu & Jing, 2022; Liu et al., 2022; Zhang & Yang, 2021; Zhang et al., 2023). Here, I first showed that GSDMC expression is increased, GSDME and PJVK expression are decreased in uterine corpus endometrial carcinoma compared to normal endometrial cells. Here, it should be noted that GSDME (DFNA5) and PJVK (DFNB59) belong to the deafness-associated genes (DFN), and their protein sequences cluster more closely together, distant from the other gasdermins (GSDMA–GSDMD) (Broz et al., 2020). Since the expression of both of these genes are decreased in tumor samples from patients with UCEC, unlike the other members of the family, they might have similar or parallel roles in tumor initiation in UCEC. Although other members of the gasdermin family might have both anti-tumor and pro-tumor functions depending on cancer type and context, GSDME and PJVK were reported to have almost always anti-tumor functions (Sarrió et al., 2021). Therefore, their decreased expression in the case of uterine corpus endometrial carcinoma might result in, at least to a certain extent, decreased anti-tumor functionality and increased tumor formation. In contrast, GSMDC has mostly pro-tumor functions in different cancer types (Sarrió et al., 2021); thus, its increased expression observed in tumors of UCEC might contribute to tumor initiation in the case of this gynecologic malignancy. In support, in our two recent studies on ovarian cancer, another gynecologic malignancy, we found that GSDME and PJVK expression are decreased, GSDMC is increased in ovarian tumors compared to normal ovaries, in parallel to what was observed in the present study (Berkel & Cacan, 2021, 2023). Therefore, it can be suggested that changes in the mRNA expression of GSDME, PJVK and GSDMC in the course of tumor formation/initiation in both ovarian cancer and UCEC might lead to similar cellular events, for instance, their insensitivity / resistance to pyroptotic cell death; however, further research is required.

Next, I found that total percentage of patients affected by mutations in gasdermin family of genes (6 genes: GSDMA-E and PJVK) is the highest in UCEC compared to other cancer types. I showed that the percentage of patients affected by mutations in GSDMD, GSDME (DFNA5) or PJVK (DFNB59) is the highest in UCEC compared to other cancer types, and the percentage of patients affected by mutations in GSDMA, GSDMB and GSDMC is the second highest in UCEC, following SKCM (skin cutaneous melanoma), among other cancer types. The highest mutation percentage among the members of the protein family was observed for GSDME, followed by GSDMC. Here, it should be highlighted that the most significant change (tumor vs normal) in the mRNA expression of gasdermin family of genes in UCEC was also observed for GSDME, possibly pointing to its relatively higher importance in the pathogenesis of UCEC compared to other gasdermin family members. Zhang et al. (2020) showed that GSDME suppresses tumour growth by activating anti-tumour immunity in some cancer models; thus, its decreased expression in UCEC similarly might result in only limited supression of tumor growth. They also reported that some cancer-related mutations in GSDME cause its loss of function (Zhang et al., 2020). Since we observed in this study that the highest percentage of mutations in UCEC patients is present in GSDME among other gasdermin family members, and that GSDME has the highest percentage of mutations in UCEC compared to other cancer types, we can state that these mutations in GSDME might lead to loss of its function, possibly leading to inefficient activation of anti-tumor immunity particularly in UCEC. Besides, this relatively higher frequency of mutations in gasdermins in UCEC compared to other cancer types might point to the need for a better mechanistic understanding of this protein family in the context of UCEC.

Later, I showed that, with the exception of GSDMA, all other members of the gasdermin family have higher mRNA expression in serous endometrial adenocarcinoma than in endometrioid endometrial adenocarcinoma. This points to the presence of histotype-dependent expression of gasdermin family in UCEC. Serous endometrial adenocarcinoma, while only accounting for around 10% of all endometrial cancers, is responsible for a disproportionate number of patient deaths (Nakayama et al., 2012). Disease-specific deaths are observed at a higher frequency in serous histological type, because it has higher rates of deep myometrial invasion, more metastatic spread to lymph nodes and peritoneal surfaces compared with endometrioid tumors of endometrial cancer (Ferriss et al., 2021; Hamilton et al., 2006). High expression of the most of gasdermin family members might possibly contribute to worse prognosis in serous endometrial adenocarcinoma compared to endometrioid endometrial adenocarcinoma; however, exact mechanism remains unknown. We have previously shown in another gynecological cancer, ovarian cancer, that high expression of GSDMC and GSDMD is associated with unfavorable progression-free survival (PFS) (Berkel & Cacan, 2021). We have also found that GSDMD transcript levels are higher in serous ovarian cancer than in endometrioid ovarian cancer (Berkel & Cacan, 2021), pointing to the histotype-dependent expression of certain gasdermin family members in gynecological cancers in general, with prognostic implications. However, combined and complex effect of the changes in the expression of all gasdermin family members should be taken into account, considering their context-dependent pro- or anti-tumor activities.

Furthermore, most significant difference in the expression of gasdermin family of genes in terms of histologic grade was observed for GSDME from grade 2 to grade 3 (increased expression; p = 1e−06). Although its expression was decreased in the course of tumor initiation (normal vs tumor), its expression was increased during tumor progression (from low to high grade), pointing to the possibly dual roles of GSDME in tumor initiation and progression in UCEC. For instance, chemotherapeutic drugs-induced pyroptosis mediated by GSDME can promote tumor progression and chemoresistance in the case of pancreatic cancer (Li et al., 2023). Similar scenario might be also in play in the context of UCEC, where increased GSDME levels might lead to tumor progression due to chemotherapeutic drugs-induced pyroptosis after patients are treated with chemotherapy following diagnosis (i.e. following tumor initiation). Further research is required to identify potentially diverse functions of GSDME in the initiation and progression of tumors of UCEC. Some other members of the gasdermin family (GSDMB, GSDMC and GSDMD) also showed generally increased expression from lower to higher tumor grades; however, their contributions to tumor progression need to better characterized.

Combined, I propose that the members of the gasdermin family might have diverse functions in tumor initiation and progression in UCEC, and that the most of these genes show histotype-dependent expression in UCEC, possibly influencing prognosis in patients with UCEC. Moreover, this analysis pointed that GSDME might be relatively more important in the context of UCEC compared to the other members of the family.

Methods

Datasets

In this study, I used TCGA-UCEC transcriptomics dataset which was accessed via ExperimentHub Bioconductor package from GEO dataset with the ID of GSE62944 (Berger et al., 2018; Cancer Genome Atlas Research Network, 2013; Morgan & Shepherd, 2022a, b; Rahman et al., 2015). Total sample size (n) of patients is 554. Sample sizes based on histologic diagnosis are: endometrioid endometrial adenocarcinoma = 401, serous endometrial adenocarcinoma = 112, and mixed serous and endometrioid = 20. Data on mutation percentages for different gasdermin genes were accessed through Genomic Data Commons (GDC) Data Portal of NCI (Berger et al., 2018; Cancer Genome Atlas Research Network, 2013; Grossman et al., 2016). More detail on the transcriptomics and mutation data used can be found elsewhere in the text or in the references (Berger et al., 2018; Cancer Genome Atlas Research Network, 2013; Grossman et al., 2016).

Data analysis and visualization

Data analysis and visualization was completely performed in R programming environment, as previously reported (Berkel, 2024a, b; R Core Team, 2022). Following R/Bioconductor packages were used throughout the analyses: tidyverse (which includes ggplot2 package) (Wickham, 2016; Wickham et al., 2019), readxl (Wickham & Bryan, 2023), ggpubr (Kassambara, 2023), ExperimentHub (Morgan & Shepherd, 2022a, b), AnnotationHub (Morgan & Shepherd, 2022a, b), SummarizedExperiment (Morgan et al., 2022), tidytext (Silge & Robinson, 2016), gt (Iannone et al., 2023), rmarkdown (Allaire et al., 2023) and knitr (Xie, 2023).

When data is not normally distributed, wilcoxon test is used to compare group means. Normality of the expression data was tested using shapiro.test() function in R (R Core Team, 2022). Gene expression count values were shown in log10 scale in y axis of plots. Gene expression data for GSDME was accessed using its alternative name (DFNA5); similarly, gene expression data for PJVK (Pejvakin) was obtained using DFNB59 as a gene name input. All missing data were removed prior to analyses. R code used in the analyses is given as a supplementary document.

Data availability

The data used in this study is publicly available as stated in Methods section.

Abbreviations

ACC:
Adrenocortical carcinoma
BLCA:
Bladder urothelial carcinoma
CESC:
Cervical squamous cell carcinoma and endocervical adenocarcinoma
CHOL:
Cholangiocarcinoma
COAD:
Colon adenocarcinoma
ESCA:
Esophageal carcinoma
GDC:
Genomic data commons
GEO:
Gene expression omnibus
GSDM:
Gasdermin
HMGB1:
High mobility group box protein 1
LUAD:
Lung adenocarcinoma
LUSC:
Lung squamous cell carcinoma
NCI:
National Cancer Institute
PAAD:
Pancreatic adenocarcinoma
PFS:
Progression-free survival
PJVK:
Pejvakin
SKCM:
Skin cutaneous melanoma
STAD:
Stomach adenocarcinoma
TCGA:
The Cancer Genome Atlas
UCEC:
Uterine corpus endometrial carcinoma
UCS:
Uterine carcinosarcoma

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Funding

CB is funded by TUBITAK 1001 program.

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Authors and Affiliations

Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Tokat, Turkey
Caglar Berkel

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CB obtained the data, performed the data analysis and visualization, wrote the paper.

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Correspondence to Caglar Berkel.

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Berkel, C. An analysis of gasdermin family of genes in UCEC with respect to malignancy status, mutation percentages and histologic diagnosis. GENOME INSTAB. DIS. 5, 105–115 (2024). https://doi.org/10.1007/s42764-024-00128-6

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Received05 February 2024
Revised08 April 2024
Accepted17 April 2024
Published06 May 2024
Issue DateJune 2024
DOIhttps://doi.org/10.1007/s42764-024-00128-6

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