CD2基因对卵巢癌肿瘤微环境中免疫浸润的作用

doi:10.12280/gjfckx.20220985

摘要/Abstract

摘要：

目的：探讨CD2基因对卵巢癌肿瘤微环境中免疫浸润的作用。方法：利用GEPIA在线工具检索CD2基因在卵巢癌中的表达情况，使用GEPIA和Kaplan-Meier plotter数据库分析CD2基因评估卵巢癌预后的价值；通过Coexpedia构建CD2基因在卵巢癌中的共表达基因网络。按评分高低筛选出关键基因，并通过GEPIA及cBioportal进一步分析CD2基因与关键基因的相关性，推测相关基因在卵巢癌中的表达及对预后的评估价值。利用TIMER分析CD2与相关基因在卵巢癌中的表达及与肿瘤微环境中的6种免疫细胞的相互关系。结果：①在癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库中，CD2基因在卵巢癌组织中的表达高于正常卵巢组织（P<0.05）。②GEPIA及Kaplan-Meier plotter均提示CD2基因高表达的患者总生存期更长（P<0.05）。③CD2基因的共表达基因有CD3D、LCK、ITK、CCL5、CD48、GZMK、PTPRC、TRAF31P3、SH2D1A、GZMA、CD247、CD52、IL10RA、CD3E、IKZF1、CD53、CD6、CXCR6及CD3G。④按评分高低排序，筛选出排序前5的关键基因，分别为CD3D、LCK、ITK、CCL5及CD48。CD2与CD3D、LCK、ITK、CCL5和CD48的表达呈正相关（P<0.05）。⑤利用TIMER分析得出CD2基因与卵巢癌中B细胞、CD4+ T细胞、CD8+ T细胞、中性粒细胞、巨噬细胞和树突状细胞的浸润情况呈正相关（P<0.05）。通过构建COX回归模型提示，巨噬细胞、中性粒细胞浸润水平与患者预后呈正相关，CD4+ T细胞浸润水平与患者预后呈负相关（P<0.05）。结论：CD2基因在卵巢癌组织中高表达，其可能通过影响肿瘤微环境中免疫细胞的浸润影响患者预后。

关键词: 卵巢肿瘤, CD2基因, 肿瘤微环境, B-淋巴细胞, 巨噬细胞, 树突细胞

Abstract:

Objective: To investigate the role of CD2 gene on immune infiltration in ovarian cancer microenvironment. Methods: GEPIA online tool was used to retrieve the expression of CD2 gene in ovarian cancer, GEPIA and Kaplan-Meier plotter databases were used to analyze the value of CD2 gene in evaluating the prognosis of ovarian cancer. Co-expression gene network of CD2 gene in ovarian cancer was constructed by Coexpedia. The key genes were screened out according to the score, and the correlation between CD2 gene and key genes was further analyzed by GEPIA and cBioportal to speculate the expression of related genes in ovarian cancer and their value for prognosis assessment. TIMER was used to analyze the expression of CD2 and related genes in ovarian cancer and the relationship between CD2 and six kinds of immune cells in tumor microenvironment. Results: ①In TCGA, the expression of CD2 gene in tumor tissue of ovarian cancer was higher than that in normal ovarian tissue (P<0.05). ②Both GEPIA and Kaplan-Meier plotter suggested that patients with high expression of CD2 gene had longer overall survival (P<0.05). ③The co-expressed genes of CD2 gene are CD3D, LCK, ITK, CCL5, CD48, GZMK, PTPRC, TRAF31P3, SH2D1A, GZMA, CD247, CD52, IL10RA, CD3E, IKZF1, CD53, CD6, CXCR6 and CD3G. ④In order of the highest score, the top five key genes were screened out, namely CD3D, LCK, ITK, CCL5 and CD48. CD2 was positively correlated with the expression of CD3D, LCK, ITK, CCL5 and CD48 (P<0.05). ⑤TIMER analysis showed that CD2 gene was positively correlated with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells in ovarian cancer (P<0.05). COX regression model suggested that the infiltration level of macrophages and neutrophils was positively correlated with the prognosis of patients, the infiltration level of CD4+ T cells was negatively correlated with the prognosis of patients(P<0.05). Conclusions: CD2 gene is highly expressed in ovarian cancer tissues, which may affect the prognosis of patients by affecting the infiltration of immune cells in tumor microenvironment.

Key words: Ovarian neoplasms, CD2 gene, Tumor microenvironment, B-lymphocytes, Macrophages, Dendritic cells

王艺璇, 张韶华, 王赞宏. CD2基因对卵巢癌肿瘤微环境中免疫浸润的作用[J]. 国际妇产科学杂志, 2023, 50(3): 290-296.

WANG Yi-xuan, ZHANG Shao-hua, WANG Zan-hong. Effect of CD2 Gene on Immune Infiltration in Tumor Microenvironment of Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2023, 50(3): 290-296.

图/表 9

图1 CD2基因在卵巢癌组织与正常组织中表达情况注：OV代表卵巢浆液性囊腺癌；红色代表卵巢癌组织（T），黑色代表正常组织（N）；Transcripts Per Million代表每千个碱基的转录每百万映射读取的转录本；*P<0.05。

图2 CD2基因的生存分析注：Months代表患者生存月份；Percent survival及Probability代表存活率；Expression代表CD2基因的表达水平：low代表低表达，high代表高表达。

图3 CD2亚细胞结构及细胞中分布情况注：免疫荧光染色后，绿色标记了CD2基因的分布情况，蓝色标记了细胞核的位置。

图4 CD2基因在卵巢癌中的部分临床病理特征注：Stage代表分期；Grade代表分化程度；Z-value代表标准分数。

图5 CD2基因在卵巢癌中的分子调控网络注：中间为CD2基因与共表达基因，周围基因是与其参与不同生物学过程或功能的基因，其中不同颜色的线代表了不同的功能。

图6 GEPIA中CD2与相关基因的相关性注：log2（TPM）代表标准化后的每千个碱基的转录每百万映射读取的转录本；R代表相关系数。

图7 CD2相关基因在卵巢癌中表达情况注：a CD3D；b LCK；c ITK；d CCL5；e CD48；OV代表卵巢浆液性囊腺癌；红色代表卵巢癌组织（T），黑色代表正常卵巢组织（N）； *P<0.05。

图8 CD2相关基因分组卵巢癌的生存分析注：Months代表患者生存月份；Probability代表存活率；Expression代表相关基因的表达水平，low代表低表达，high代表高表达。

表1 卵巢癌患者总生存期影响因素的COX比例风险回归模型分析

影响因素	B	SE	Wald χ²	HR	95%CI	P
B细胞	-1.906	0.570	4.470	0.149	0.000~60.750	0.534
CD8+ T细胞	-3.238	0.700	81.438	0.039	0.001~1.643	0.089
CD4+ T细胞	-15.241	2.973	13.370	0.000	0.000~0.000	0.000
巨噬细胞	9.442	1.078	83.262	12 612.838	60.580~2 626 013.740	0.001
中性粒细胞	9.025	0.983	15.302	8 305.325	1.521~45 359 183.998	0.040
树突状细胞	-0.922	0.566	4.469	0.398	0.004~39.274	0.694

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