成纤维细胞生长因子受体2在肾透明细胞癌中的表达及意义

doi:10.19723/j.issn.1671-167X.2022.04.008

摘要/Abstract

摘要：

目的: 研究成纤维细胞生长因子受体2(fibroblast growth factor receptor 2，FGFR2)在肾透明细胞癌(clear cell renal cell carcinoma，ccRCC；or kidney renal clear cell carcinoma，KIRC)中的表达情况，对FGFR2的表达与ccRCC临床病理特征及预后关系进行分析，并研究FGFR2的表达与其他分子之间作用关系，探讨其在ccRCC发生发展中的作用。方法: 从肿瘤基因图谱(The Cancer Genome Atlas, TCGA)数据库及基因表达综合(Gene Expression Omnibus，GEO)数据库中下载ccRCC患者的基因表达及临床信息资料，进行转化及整理，并收集北京大学第一医院泌尿外科104例临床ccRCC样本及癌旁正常组织样本，进行免疫组织化学染色(immunohistochemistry, IHC)，对染色结果进行评分，从而比较ccRCC和癌旁正常组织中FGFR2的蛋白表达情况；采用实时荧光定量聚合酶链反应(quantify real-time polymerase chain reaction，qRT-PCR)检测正常的肾上皮细胞系(293)和肾细胞癌细胞系(786-O、769-P、OSRC-2、Caki-1、ACHN、A498)中FGFR2的mRNA表达水平；对数据库中的ccRCC患者进行进一步分析，研究FGFR2表达与ccRCC患者临床病理特征(包括TNM分期和病理分级)以及生存预后的关系，分析ccRCC患者中FGFR2表达与B细胞、T细胞、自然杀伤(natural killer，NK)细胞及中性粒细胞浸润的关系，并使用生物交互数据集通用存储库(Biological General Repository for Interactionh Datasets，BioGRID)构建蛋白质相互作用(protein-protein interaction，PPI)网络，利用网络研究与FGFR2蛋白相互作用的分子。结果: 在TCGA数据库中，相较于正常组织样本，FGFR2在ccRCC组织样本中表达下调，在GEO数据库中的表达也呈现出这一差异，并且FGFR2在ccRCC临床样本及ccRCC细胞系中表达下调，此外，FGFR2表达水平与ccRCC高分级分期相关，与ccRCC患者较好的预后相关，并且FGFR2表达与B细胞、T细胞、NK细胞及中性粒细胞浸润无明显相关关系。PPI网络显示FGFR2蛋白与某些分子间存在相互作用。结论: 本研究揭示了FGFR2与ccRCC发生发展的潜在作用关系，提示FGFR2可能作为ccRCC患者的预后标志物和潜在治疗靶点。

关键词: 成纤维细胞生长因子受体2, 肾透明细胞癌, 生物标志物

Abstract:

Objective: To investigate the expression of fibroblast growth factor receptor 2 (FGFR2) in clear cell renal cell carcinoma (ccRCC; or kidney renal clear cell carcinoma, KIRC), to analyze the relationship between the expression of FGFR2 and the clinical pathological features and prognosis of ccRCC, to study the relationship between the expression of FGFR2 and other molecules, and to explore its role in the development of ccRCC. Methods: Gene expressional and clinical information of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus(GEO) database. Next, the data were transformed and collated. In the study, 104 clinical ccRCC samples and corresponding paracancerous normal tissue samples were collected from Department of Urology, Peking University First Hospital. Immunohistochemistry (IHC) was performed and the staining results were scored, so as to compare the expression of FGFR2 in ccRCC and paracancerous normal tissues. Besides, quantify real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression level of FGFR2 in normal renal epithelial cell lines (293) and ccRCC cell lines (786-O, 769-P, OSRC-2, Caki-1, ACHN, and A498). In addition, the relationship between FGFR2 expression and clinical pathological characteristics (including TNM staging and pathological grading) and survival prognosis in ccRCC patients was further analyzed. Furthermore, the relationship between FGFR2 expression and B cells, T cells, natural killer (NK) cells and neutrophil infiltration in the ccRCC patients was analyzed, and the Biological General Repository for Interactionh Datasets (BioGRID) was used to builds protein-protein interaction (PPI) networks to study molecules that interacted with the FGFR2 protein. Results: In the TCGA database, the expression of FGFR2 was down-regulated in ccRCC tissue samples compared with normal tissue samples, and the expression in the GEO database also showed this differences. Furthermore, FGFR2 expression was downregulated in ccRCC clinical samples and ccRCC cell lines, compared with corresponding paracancerous normal tissue or normal renal epithelial cell lines. In addition, FGFR2 high expression was associated with earlier, lower-level ccRCC and was associated with a better prognosis in the patients with ccRCC. Moreover, FGFR2 expression was not significantly related to B cells, T cells, NK cells and neutrophil infiltration, and the PPI network showed that FGFR2 protein interacted with certain molecules. Conclusion: Our work sheds light on the potential role of FGFR2 in the development of ccRCC, suggesting that FGFR2 may serve as a prognostic marker and potential therapeutic target for patients with ccRCC.

Key words: Fibroblast growth factor receptor 2, Clear cell renal cell carcinoma, Biomarker

中图分类号:

蔡天玉,朱振鹏,徐纯如,吉星,吕同德,郭振可,林健. 成纤维细胞生长因子受体2在肾透明细胞癌中的表达及意义[J]. 北京大学学报（医学版）, 2022, 54(4): 628-635.

Tian-yu CAI,Zhen-peng ZHU,Chun-ru XU,Xing JI,Tong-de LV,Zhen-ke GUO,Jian LIN. Expression and significance of fibroblast growth factor receptor 2 in clear cell renal cell carcinoma[J]. Journal of Peking University (Health Sciences), 2022, 54(4): 628-635.

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Items	Low expression of FGFR2(n=269)	High expression of FGFR2(n =270)	P
T stage, n (%)			0.001
T1	117 (21.7)	161 (29.9)
T2	46 (8.5)	25 (4.6)
T3	100 (18.6)	79 (14.7)
T4	6 (1.1)	5 (0.9)
N stage, n (%)			1.000
N0	128 (49.8)	113 (44.0)
N1	9 (3.5)	7 (2.7)
M stage, n (%)			1.000
M0	216 (42.7)	212 (41.9)
M1	39 (7.7)	39 (7.7)
Pathologic stage, n (%)			0.002
Stage Ⅰ	115 (21.5)	157 (29.3)
Stage Ⅱ	36 (6.7)	23 (4.3)
Stage Ⅲ	74 (13.8)	49 (9.1)
Stage Ⅳ	42 (7.8)	40 (7.5)
OS event, n (%)			0.009
Alive	168 (31.2)	198 (36.7)
Dead	101 (18.7)	72 (13.4)
Age, M (IQR)	61 (52, 70)	60 (51, 69)	0.241

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