膜穿孔蛋白E在上皮性卵巢癌组织中的表达水平及其临床意义

doi:10.13481/j.1671-587X.20230220

Abstract

Abstract:

Objective To discuss the expression level of gasdermin E （GSDME） in the epithelial ovarian cancer （EOC） tissue， and to clarify the effect of GSDME on the occurrence and development of EOC. Methods The expressions of GSDME mRNA in normal tissue and EOC tissue was detected by R language based on the Cancer Genome Atlas （TCGA） and Genotype-Tissue Expression （GTEx） Databases；the correlation between the expression level of GSDME and the occurrence of EOC was analyzed. The difference analysis， Gene Ontology （GO） analysis，Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway richment analysis， Gene Set Enrichment analysis （GSEA）， protein-protein interaction （PPI） network， HUB gene interaction network，and immune infiltration analysis were used to discuss the genes and signaling pathways associated with GSDME and their effects on the occurrence and development of EOC. The pathological tissue sections of 40 EOC patients were collected and divided into low-grade group （well-differentiated and moderately-differentiated，n=24） and high-grade group （poorly differentiated，n=16） based on the pathological grades； according to the sensitivity to cisplatin （DDP）， the pathological tissue sections were divided into DDP resistant group and DDP sensitive group. In addition， 5 tissue sections of normal ovary， benign ovarian tumor， and 5 tissue sections of borderline ovarian carcinoma were collected as controls. The expression intensities of GSDME in all the tissue sections were detected by immunohistochemistry （IHC） method. Besides， 10 pairs of fresh ovarian cancer and paracancerous tissues were selected， and the expression levels of GSDME protein in the samples in two groups were detected by Western blotting method. The ovarian cancer Skov3 cells and Skov3/DDP cells were cultured in vitro， and the expression levels of GSDME protein in the cells were detected by Western blotting method and the relationship between the expression level and DDP-resistance of ovarian cancer was analyzed. Results The analysis results of unpaired samples in the TCGA and GTEx Databases showed that compared with normal ovarian tissue， the expression level of GSDME mRNA in EOC tissue was significantly decreased （P<0.05）， and the expression of GSDME mRNA in EOC tissue in high-grade group was higher than that in low-grade group（P<0.05）.The GSDME single gene difference analysis results showed that there were 460 up-regulated and 329 down-regulated genes |（Log₂ fold charge（FC）|>1，P<0.05）.The functional enrichment and immune infiltration analysis results showed that high expression of GSDME could upregulate the activities of humoral immunie response pathways，leukocyte migration pathway and immunoglobulin complex pathway mediated by circulating immunoglobulin and promote the infiltration of immune cells in tumor microenvironment. The IHC staining results showed that GSDME was related to the pathological grade and drug resistance of EOC； the expression intensity of GSDME in EOC tisssue in DDP sensitive group was higher than that in DDP resistant group（P<0.05）.The Western blotting results showed that compared with paracancerous tissue， the expression level of GSDME protein in EOC tissue was significantly decreased （P<0.05）； compared with Skov3 cells， the expression level of GSDME protein in the Skov3/DDP cells was significantly decreased （P<0.05）. Conclusion GSDME is closely related to the malignancy and cisplatin resistance of EOC. The low expression of GSDME is a key factor leading to the decreasing of tumor immune infiltration， EOC deterioration and resistance.GSDME may be a potential molecular target for the treatment of EOC.

Key words: Gasdermin E, Epithelial ovarian neoplasm, Gene expression, Bioinformatic

CLC Number:

R737.31

Mengmeng CHEN,Junyu CHEN,Yan GAO,Zhengxuan FANG,Shuhua ZHAO,Jingying ZHENG,Shuxiang LIU. Expression level of gasdermin E in epithelial ovarian cancer tissue and its clinical significance[J].Journal of Jilin University(Medicine Edition), 2023, 49(2): 440-451.

Figures/Tables 16

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ID	ES	NES	P	FDR
REACTOME_GPCR_LIGAND_BINDING	0.553	0.652	0.009	0.005
REACTOME_EXTRACELLULAR_MATRIX_ORGANIZATION	0.702	3.418	0.009	0.005
KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION	0.566	2.733	0.009	0.005
REACTOME_ANTI_INFLAMMATORY_RESPONSE_FAVOURING_ LEISHMANIA_PARASITE_INFECTION	0.630	2.963	0.009	0.005
REACTOME_IMMUNOREGULATORY_INTERACTIONS_BETWEEN_A_ LYMPHOID_AND_A_NON_LYMPHOID_CELL	0.652	3.010	0.009	0.005

ID	ES	NES	P	FDR
WP_ELECTRON_TRANSPORT_CHAIN_OXPHOS_SYSTEM_IN_MITOCHONDRIA	－0.748	－3.115	0.009	0.005
WP_CYTOPLASMIC_RIBOSOMAL_PROTEINS	－0.838	－3.454	0.009	0.005
REACTOME_RRNA_PROCESSING	－0.672	－3.145	0.009	0.005
REACTOME_SIGNALING_BY_ROBO_RECEPTORS	－0.555	－2.611	0.009	0.005
REACTOME_TRANSLATION	－0.628	－3.094	0.009	0.005

Ontology	ID	Description	Gene ratio	BgRatio	Adjusted P	q
BP	GO:0000395	mRNA 5'-splice site recognition	5/359	29/18 670	0.012	0.011
BP	GO:0006376	mRNA splice site selection	5/359	53/18 670	0.084	0.076
BP	GO:0045292	mRNA cis splicing, via spliceosome	5/359	56/18 670	0.096	0.087
BP	GO:0002455	humoral immune response mediated by circulating immunoglobulin	13/359	150/18 670	0.001	0.001
BP	GO:0050900	leukocyte migration	21/359	499/18 670	0.028	0.025
CC	GO:0019814	immunoglobulin complex	14/387	159/19 717	0.001	0.001
BP	GO:0045765	regulation of angiogenesis	18/359	383/18 670	0.021	0.019

Clinical feature	n （η/%）	GSDME		χ2	P
Clinical feature	n （η/%）	Positive expression	Negative expression	χ2	P
Age（year）
<53	17（42.5）	8	9
≥53	23（57.5）	10	13	0.051	0.822
FIGO stage
Ⅰ-Ⅱ	19（47.5）	9	10
Ⅲ-Ⅳ	21（52.5）	9	12	0.082	0.775
Tumor size
≤10 cm	19（47.5）	8	11
>10 cm	21（52.5）	10	11	0.123	0.726
EOC type
Type Ⅰ	21（52.5）	10	11
Type Ⅱ	19（47.5）	8	11	0.123	0.726
Pathological grade
Low level	16（40.0）	11	5
High level	24（60.0）	7	17	6.077	0.014
Ascites volume
<500 mL	21（52.5）	11	10
≥500 mL	19（47.5）	7	12	0.973	0.324

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Expression level of gasdermin E in epithelial ovarian cancer tissue and its clinical significance

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