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Nan Fang Yi Ke Da Xue Xue Bao.
2021 Apr 20; 41(4): 555–561.
Language:
Chinese
|
English
ENTPD5在上皮性卵巢癌组织中高表达：基于Oncomine数据库及生物信息学方法
ENTPD5 gene is highly expressed in epithelial ovarian cancer: analysis based on Oncomine database and bioinformatics
,
1,
*
,
1
,
1
,
1
,
1
,
2
and
2,
*
王 卉
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
陈 学平
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
陈 运
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
曹 颖诗
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
陈 瑶
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
刘 国炳
南方医科大学南方医院妇产科，广东 广州 510515,
Southern Medical University of Nanfang Hospital, Obstetrics and Gynecology Department, Guangzhou 510515, China
黄 莉萍
南方医科大学南方医院妇产科，广东 广州 510515,
Southern Medical University of Nanfang Hospital, Obstetrics and Gynecology Department, Guangzhou 510515, China
南方医科大学第一临床医学院，广东 广州 510515,
The first clinical college of Southern Medical University, Guangzhou 510515, China
南方医科大学南方医院妇产科，广东 广州 510515,
Southern Medical University of Nanfang Hospital, Obstetrics and Gynecology Department, Guangzhou 510515, China
*
P
< 0.05,
**
P
< 0.01
vs
normal tissue.
3
ENTPD5的表达与卵巢癌患者的临床病理特征之间的关系
Association of ENTPD5 expression with clinicopathological characteristics of 50 patients with EOC (
χ
2
-test)
|
Clinicopathological features
|
ENTPD5 expression
|
|
Low expression
|
High expression
|
P
|
|
Age (year)
|
< 56
|
13
|
13
|
0.01
|
|
≥56
|
4
|
20
|
|
FIGO staging
|
Ⅰ+Ⅱ
|
5
|
8
|
0.74
|
|
Ⅲ+Ⅳ
|
12
|
25
|
|
CA125 (U/mL)
|
< 600
|
12
|
22
|
0.78
|
|
≥600
|
5
|
11
|
|
Lymph node metastasis
|
Positive
|
6
|
5
|
0.15
|
|
Nagetive
|
11
|
28
|
|
Omentum metastasis
|
Positive
|
12
|
21
|
0.62
|
|
Nagetive
|
5
|
12
|
3. 讨论
虽然近年来卵巢癌的治疗取得一些进展
[
10
]
，但由于其发病隐匿，多数患者确诊时已处于肿瘤中晚期，甚至伴有局部或全身转移，五年生存率低下
[
11
-
13
]
。寻找与卵巢癌发病相关的有效生物标志物，提高卵巢癌的早期诊断，对改善其预后具有重要意义。
ENTPD5主要存在于内质网中，编码内质网的核苷酸水解酶，在其家族中唯一被描述为原癌蛋白成员，介导细胞内核苷酸的分解代谢
[
14
]
，通过PI3K信号通路的激活，以及Mut-p53与Sp1-ENTPD5启动子区相互作用两条途径过度表达后
[
15
]
，在多个层次参与细胞过程，抑制肿瘤细胞凋亡，促进肿瘤细胞发生、发展和转移，ENTPD5表达的下调可以降低肿瘤细胞的存活能力
[
8
]
。Villar等
[
16
]
在前列腺癌的相关研究中发现，ENTPD5表达水平与前列腺病变程度呈正相关性。2016年PNAS研究报道，作为突变的肿瘤抑制基因p53的靶分子，ENTPD5可以被突变的p53调控以调节胰腺癌的发展和转移
[
17
]
。此外，在黑色素瘤、宫颈癌、乳腺癌、结肠癌等多项研究中亦发现ENTPD5呈高表达，提示ENTPD5可能参与癌症的发生发展
[
6
-
8
]
。
目前，国内外尚未见ENTPD5与卵巢癌相关性的研究报道，ENTPD5是否可以成为上皮性卵巢癌早期诊断的新靶点值得进一步研究。基于上述研究背景，首先我们通过Oncomine及TCGA数据库证明，ENTPD5在上皮性卵巢癌组织中的表达显著高于正常卵巢组织，与患者生存呈负相关。进一步使用GSEA软件分析发现，ENTPD5参与B、T细胞介导的信号通路、ABC转运蛋白、WNT信号通路、胰岛素信号通路以及糖降解等过程。其中，在糖代谢的异常以及Ⅱ型糖尿病的发生过程中，机体长期暴露于高水平的血糖环境，可引起RasMAPK和PI 3-K-mTOR途径的激活，促进卵巢癌细胞增殖和疾病进展
[
18
-
19
]
。ABC转运蛋白也被发现具有促进肿瘤细胞的增殖、转移、免疫逃避、肿瘤耐药及维持肿瘤细胞低分化程度的功能
[
20
-
23
]
。WNT / PCP信号的激活被证实可通过增强上皮性卵巢癌细胞的自我更新和持续迁移、侵袭能力
[
24
-
27
]
。以上结果表明，ENTPD5可能通过上述多条通路参与上皮性卵巢癌的发生和发展。分析ENTPD5与上皮性卵巢癌免疫浸润的相关性发现，ENTPD5的表达与NK细胞、肥大细胞、嗜酸性粒细胞呈显著负相关。此类细胞可通过裂解、分泌或结合肿瘤坏死因子，介导肿瘤干细胞的选择和分化，抑制肿瘤细胞向远处组织的增殖、迁移和定植
[
28
-
32
]
。由此猜测，ENTPD5也可能通过影响肿瘤细胞局部微环境的方式，参与上皮性卵巢癌的发生和发展。通过RT-qPCR、Western blot及免疫组化等实验方法，对上述结论进行验证，证实ENTPD5在上皮性卵巢癌组织中表达显著增高。
综上所述，我们通过使用生物信息学手段深入挖掘上皮性卵巢癌组织中ENTPD5表达信息以及实验验证相结合的手段，证明ENTPD5在上皮性卵巢癌组织中表达显著增高，为ENTPD5成为上皮性卵巢癌早期诊断的新靶点提供了理论支持证据。相对于传统的单个实验样本的研究，肿瘤数据库具有样本量大、可信度高的优点，对疾病的诊治可提供有力的生物学依据，可为进一步探索ENTPD5基因与上皮性卵巢癌的关系奠定基础。
Funding Statement
国家自然科学基金青年科学基金（81703078）；广东省科技计划项目（2017A010105025）
Supported by Youth Program of National Natural Science Foundation of China (81703078)
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