含WW结构域的泛素E3连接酶1调节卵巢癌肿瘤微环境中的免疫浸润
[WW domain-containing ubiquitin E3 ligase 1 regulates immune infiltration in tumor microenvironment of ovarian cancer].
作者信息
Guo Xiaojuan, DU Ruijuan, Chen Liping, Guo Kelei, Zhou Biao, Bian Hua, Han Li
机构信息
Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang 473004, China.
Henan Provincial Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang 473004, China.
出版信息
Nan Fang Yi Ke Da Xue Xue Bao. 2025 May 20;45(5):1063-1073. doi: 10.12122/j.issn.1673-4254.2025.05.20.
OBJECTIVES
To explore the association of the expression of WW domain-containing ubiquitin E3 ligase 1 (WWP1) with immune infiltration in tumor microenvironment (TME) of ovarian cancer.
METHODS
Ovarian cancer patient data from The Cancer Genome Atlas (TCGA) were used to analyze the association of WWP1 expression with patient prognosis. TISCH2 was utilized to analyze the changes in immune cell subtypes in TME of metastatic tumor and after chemotherapy. The impact of WWP1 on immune cell infiltration, somatic copy number alterations of WWP1 and evolution of immune cell subtypes was evaluated using TIMER and TIGER pseudo-time analysis. A deep learning model was used to analyze TCGA pathological images to investigate the effect of WWP1 on TME of ovarian cancer. RNA-seq analysis was conducted to identify the differentially expressed genes in WWP1-overexpressing SKOV3 cells and validate immune infiltration. Multicolor immunofluorescence assay was used to analyze the immune markers in SKOV3 and SKOV3/DDP cell xenografts in nude mice.
RESULTS
The patients with high WWP1 expression levels had significantly lower overall survival rate (=0.0012). High WWP1 expression levels and Stage IV disease were both associated with a poor prognosis (<0.05). In metastatic ovarian cancer or after chemotherapy, the percentages of malignant tumor cells and tumor-associated fibroblasts increased in the TME, accompanied by elevated WWP1 levels. WWP1 expression level was positively correlated with pro-tumorigenic immunosuppressive cells (=0.1323-0.3955, <0.05) and negatively with tumor-inhibiting immune cells (=-0.1949- -0.1333, <0.05). Specific copy number alterations of WWP1 also influenced CD8 T cell percentage and neutrophil infiltration levels in the TME. RNA-seq analysis of WWP1-overexpressing SKOV3 cells and immunofluorescence assay of the tumor-bearing mice yielded findings consistent with those of bioinformatics analysis.
CONCLUSIONS
WWP1 may serve as a prognostic biomarker and a potential target for immune regulation in the TME of ovarian cancer.
目的
探讨含WW结构域的泛素E3连接酶1（WWP1）的表达与卵巢癌肿瘤微环境（TME）中免疫浸润的关系。
方法
利用癌症基因组图谱（TCGA）中的卵巢癌患者数据，分析WWP1表达与患者预后的关系。利用TISCH2分析转移性肿瘤及化疗后TME中免疫细胞亚型的变化。使用TIMER和TIGER伪时间分析评估WWP1对免疫细胞浸润、WWP1的体细胞拷贝数改变及免疫细胞亚型演变的影响。使用深度学习模型分析TCGA病理图像，以研究WWP1对卵巢癌TME的影响。进行RNA测序分析，以鉴定过表达WWP1的SKOV3细胞中差异表达的基因，并验证免疫浸润情况。采用多色免疫荧光分析法分析裸鼠体内SKOV3和SKOV3/DDP细胞异种移植物中的免疫标志物。
结果
WWP1表达水平高的患者总生存率显著降低（=0.0012）。WWP1高表达水平和IV期疾病均与预后不良相关（<0.05）。在转移性卵巢癌或化疗后，TME中恶性肿瘤细胞和肿瘤相关成纤维细胞的百分比增加，同时WWP1水平升高。WWP1表达水平与促肿瘤免疫抑制细胞呈正相关（=0.1323 - 0.3955，<0.05），与抑肿瘤免疫细胞呈负相关（=-0.1949 - -0.1333，<0.05）。WWP1的特定拷贝数改变也影响TME中CD8 T细胞百分比和中性粒细胞浸润水平。对过表达WWP1的SKOV3细胞进行RNA测序分析以及对荷瘤小鼠进行免疫荧光分析，结果与生物信息学分析一致。
结论
WWP1可能作为卵巢癌TME中的预后生物标志物和免疫调节的潜在靶点。
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