EPPK1蛋白在子宫内膜癌中的表达及其分子病理学意义

Expression of EPPK1 in endometrial carcinoma tissues and its molecular pathological significance

摘要

目的 探讨epiplakin 1(EPPK1)在子宫内膜癌中的表达特征及其潜在临床意义。方法 本研究基于TCGA数据库,应用R语言对EPPK1在子宫内膜癌中的mRNA表达进行差异分析,评估其表达水平与患者年龄、病理分级等的相关性。采用Kaplan-Meier生存分析探讨EPPK1表达与总生存期(OS)和无进展生存期(PFS)之间的相关性。利用组织芯片对子宫内膜癌及癌旁组织的EPPK1蛋白表达进行免疫组化检测,并依据阳性细胞比例和染色强度进行评分,采用Mann-Whitney U检验进行统计分析。借助UALCAN和cBioPortal数据库,分析EPPK1在蛋白层面的表达模式及基因变异情况,进一步通过TIMER2.0平台评估其在多种肿瘤中的表达趋势。结果 EPPK1在子宫内膜癌组织中的表达显著上调,并与患者年龄及肿瘤分级密切相关。EPPK1高表达组患者呈现较差的OS(HR=1.91,95%CI:1.26~2.09,P=0.020)与PFS(HR=1.51,95%CI:1.07~2.14,P=0.020)。免疫组化结果进一步证实其在癌组织中蛋白表达水平上调。EPPK1的表达与多条信号通路关键蛋白表达存在潜在关联,并在多种肿瘤中具有较高表达趋势。结论 EPPK1在子宫内膜癌中呈高表达状态,可能参与肿瘤进展,具有潜在的诊断与预后生物标志物价值。

Abstract

Objective To investigate expression profile of epiplakin 1 (EPPK1) in endometrial carcinoma and its potential clinical significance. Methods Based on The Cancer Genome Atlas (TCGA) database,using the R Programming Language software,analysis of mRNA expression levels of EPPK1 in endometrial carcinoma tissues was conducted to analyze correlations between EPPK1 expression and clinical-pathological parameters such as patient age and tumor grade.Kaplan-Meier survival analysis was performed to explore associations of EPPK1 expression with overall survival (OS) and progression-free survival (PFS).To further validate EPPK1 expression status in endometrial carcinoma tissues,immunohistochemistry (IHC) for tissue microarrays containing endometrial carcinoma tissues and adjacent non-cancerous tissues was conducted and scored based on proportion of the positive cells and staining intensity.Statistical analysis was performed using Mann-Whitney U test.Additionally,UALCAN and cBioPortal databases were used to characterize EPPK1 expression patterns and gene alterations,and TIMER2.0 database was further employed to assess its expression trends across multiple cancer types. Results EPPK1 was significantly upregulated in endometrial carcinoma tissues and closely correlated with patient age and tumor grade,and the patients with high EPPK1 expression exhibited poor OS (HR=1.91,95%CI:1.26-2.09,P=0.020) and PFS (HR=1.51,95%CI:1.07-2.14,P=0.02).IHC further confirmed upregulation of EPPK1 expression level in endometrial carcinoma tissues.Moreover,EPPK1 expression was potentially associated with expression of key proteins in multiple signaling pathways and exhibited a high expression trend across many different cancer types. Conclusion EPPK1 is highly expressed in endometrial carcinoma tissues and may participate in tumorigenesis and progression.It holds promise as a potential diagnostic and prognostic biomarker.

关键词

子宫内膜癌 / 分子分型 / 免疫浸润 / EPPK1 / 组织芯片

Key words

endometrial carcinoma / molecular typing / immune infiltration / EPPK1 / tissue microarray

参考文献

[1] Sung H, Ferlay J, Siegel R L, et al. Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.

[2] Liang B, Tan J, Li J, et al. Epidemiology,molecular typing,microbiome-immune interactions and treatment strategies of endometrial cancer:a review[J]. Front Immunol, 2025, 16: 1595638.

[3] Panyavaranant P, Rattanachaipipat J, Manchana T. Clinicopathological characteristics and survival outcomes of women aged ≤45 and >45 years with endometrial adenocarcinoma in tertiary referral hospital:a 21-year cohort study[J]. BMJ Open, 2025, 15(1): e089434.

[4] Zouzoulas D, Tsolakidis D, Sofianou I, et al. Molecular classification of endometrial cancer:Impact on adjuvant treatment planning[J]. Cytojournal, 2024, 21: 47.

[5] Kühtreiber H, Drexler C, Salek M, et al. Epiplakin expression is lost in psoriatic skin lesions and is downregulated by IFN-γ in ex vivo skin cultures[J]. Front Cell Dev Biol, 2025, 13: 1617737.

[6] Yang L, Huang W, Bai X, et al. Androgen dihydrotestosterone promotes bladder cancer cell proliferation and invasion via EPPK1-mediated MAPK/JUP signaling[J]. Cell Death Dis, 2023, 14(6): 363.

[7] Kumar U, Castellanos-Uribe M, May ST, et al. Adaptive resistance is not responsible for long-term drug resistance in a cellular model of triple negative breast cancer[J]. Gene, 2023, 850: 146930.

[8] Jia J, Yu L. METTL3-mediated m6A modification of EPPK1 to promote the development of esophageal cancer through regulating the PI3K/AKT pathway[J]. Environ Toxicol, 2024, 39(5): 2830-2841.

[9] Ma D, Pan Z, Chang Q, et al. KLF5-mediated Eppk1 expression promotes cell proliferation in cervical cancer via the p38 signaling pathway[J]. BMC Cancer, 2021, 21(1): 377.

[10] Makker V, MacKay H, Ray-Coquard I, et al. Endometrial cancer. Nat Rev Dis Primers 2021, 7(1): 88.

[11] 张莉莉, 谢丽娟. 血清S100A8和PD-L1联合超声检测在子宫内膜癌诊断及预后中的价值分析[J]. 中国妇幼健康研究, 2024, 35(10): 79-84.

[12] Halim C E, Deng S, Crasta K C, et al. Interplay between the cytoskeleton and DNA damage response in cancer progression[J]. Cancers (Basel), 2025, 17(8): 1378.

[13] Yan X L, Wu J J, Ti H B, et al. Decoding TAGLN2 in cancer:the molecular linchpin bridging actin remodelling,immune dysregulation and therapeutic challenges[J]. Int J Biol Macromol, 2025, 321(Pt 2): 146062.

[14] Arimura K, Kammer M, Rahman S M J, et al. Elucidating the role of EPPK1 in lung adenocarcinoma development[J]. BMC Cancer, 2024, 24(1): 441.

[15] Qiao Z, Dai C, Wang Z, et al. Epiplakin1 promotes the progression of esophageal squamous cell carcinoma by activating the PI3K-AKT signaling pathway[J]. Thorac Cancer, 2022, 13(8): 1117-1125.

[16] Liu L, Yuan S, Yao S, et al. EPPK1 as a Prognostic Biomarker in Type Ⅰ Endometrial Cancer and Its Correlation with Immune Infiltration[J]. Int J Gen Med, 2024, 17: 1677-1694.

[17] 李乐赛, 戴淼, 薛艳, 等. 妇科恶性肿瘤保器官的临床诊治[J]. 中国妇幼健康研究, 2025, 36(9): 68-74.

[18] Wang C W, Firdi N P, Lee Y C, et al. Deep learning for endometrial cancer subtyping and predicting tumor mutational burden from histopathological slides[J]. npj Precision Oncology, 2024, 8(1): 287.

[19] Hu D, Zhao J, Wu M, et al. Microbial interactions induce the mutational signature of mismatch repair deficiency in colorectal cancer and associated with EPPK1 mutations[J]. Cancer Lett, 2025, 625: 217807.

[20] Berek J S, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer:2023[J]. Int J Gynaecol Obstet, 2023, 162(2): 383-394.

[21] Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma[J]. Int J Gynecol Cancer, 2021, 31(1): 12-39.

[22] Tabatabaee A, Nafari B, Farhang A, et al. Targeting vimentin:a multifaceted approach to combating cancer metastasis and drug resistance[J]. Cancer Metastasis Rev, 2024, 43(1): 363-377.

基金资助

国家自然科学基金面上项目(81571393)