摘要
背景和目的：
EZH2 (enhancer of zeste homolog 2)是1996年发现的一种新的人类基因,是果蝇zeste基因增强子的人类同源物,是PcG (Polycomb Group)基因家族的重要成员之一。在PcG基因家族中,EZH2起着核心作用。人类PcG基因是一个基因大家族,首次发现于胚胎形成的过程中,在胚胎发育、细胞周期、血细胞生成和x染色体失活调节中起关键性作用。EZH2又称作ENX-1,是早期胚胎发育中所表达的一种蛋白,在胚胎发育后期限制性表达于中枢和外周神经系统及胎儿的造血系统。在某些肿瘤中有过表达现象,包括前列腺癌、乳腺癌,与肿瘤的发展和转归密切相关。前列腺癌在男性是癌相关死亡的主要死因,虽然有效的外科及放射治疗在临床上用于局限性前列腺癌,转移性前列腺癌仍然不能治愈。
本课题旨在探讨EZH2及PTEN蛋白在前列腺癌及前列腺增生症中的表达状况。探讨EZH2蛋白在前列腺癌发生发展中的作用,为前列腺癌的诊断、治疗及预后判断提供新的生物指标。
方法：
采用组织芯片,应用免疫组化方法检测EZH2和PTEN (phosphatase and tensin homology deleted on chromosome ten, PTEN)在77例前列腺癌和30例良性前列腺增生症中的表达状况,并探讨它们与临床各病理特征的关系。
结果：
EZH2在前列腺癌中阳性率为89.6%,其在前列腺增生症中的阳性率为66.7%,两组中的差异有统计学意义(P<0.05)。前列腺癌中细胞质EZH2的表达明显高于前列腺增生(P<0.01),且与Gleason分级呈正相关。EZH2与患者的临床分期、年龄、术前血清PSA及cPSA等均无相关。前列腺癌中EZH2和PTEN的表达呈明显负相关(rs=-0.373,P<0.01)。
结论：
(1)前列腺癌中EZH2的表达明显高于前列腺增生症,EZH2可能与前列腺癌的发生发展有关。
(2)EZH2不仅在前列腺癌细胞的细胞核中表达,且大部分伴有细胞质的表达。EZH2在前列腺增生症组织染色较弱,在细胞核中表达,细胞质中几乎无表达。推测细胞质中高表达EZH2与前列腺癌的发生密切相关。
(3)前列腺癌胞质中EZH2蛋白的表达与Gleason分级呈显著正相关,实验中还观察到前列腺癌组织中一些轮廓较好腺体中EZH2不着色,而周围不规则腺体及弥漫排列的癌细胞EZH2表达较好,提示EZH2可能与肿瘤分化有关,推测EZH2蛋白的表达与前列腺癌的预后相关。
(4)EZH2是一种转录抑制因子,其在前列腺癌的表达与PTEN呈明显负相关,推测前列腺癌中PTEN可能是被EZH2抑制的抑癌基因之一。PTEN在前列腺癌中表达减少,两者共同促进癌的发生及发展。
(5)前列腺癌中术前血清PSA及CPSA均显著高于前列腺增生症患者,作为前列腺癌筛查、鉴别诊断及术后复查的常用指标,在前列腺癌中该2项指标与EZH2均无相关性。
(6)前列腺癌中EZH2蛋白表达与患者年龄、临床分期、术前血清PSA水平及cPSA均无相关性(P均>0.05)。
Background and Objective:Human PcG (Polycomb Group) gene is a large gene family, it was first discovered in the process of embryo formation, and played a crucial role in embryonic development, cell cycle, blood cell formation and x chromosome inactivated regulation. EZH2 (enhancer of zeste homolog 2), also named ENX-1,is a key member of the PcG gene family, which was discovered as a new human gene that is the human homologue of the Drosophila protein Enhancer of Zeste in 1996. It expressed in early embryogenesis, and only restricted expressed in the latter stage of embryogenesis in central and peripheral nervous system and fetal hematopoietic system. EZH2 gene over-expressed in many tumors, such as prostate cancer and breast cancer, which was closely correlated with the occurrence and development of the tumor. Prostate cancer is the most frequent cause of death among all men cancer patients, and there are currently no effective therapeutic approaches for the metastatic prostate cancer in spite of advances in surgery and radiotherapy. This study aims to investigate the expression of EZH2 and PTEN protein in prostate cancer and benign prostatic hyperplasia. To explore the roles of EZH2 in the development and progression of prostate cancer, which might provide a new biological marker in the prostate cancer diagnosis, treatment and prognosis.
Methods:Using tissue microarray, immunohistochemical staining to detect the expression of EZH2 and PTEN (phosphatase and tensin homology deleted on chromosome ten, PTEN) in 77 cases of prostate cancer and 30 cases of benign prostatic hyperplasia and to explore their various pathological features and clinical relationship.
Results:EZH2 in prostate cancer-positive rate was 89.6%, in benign prostatic hyperplasia-positive rate was 66.7%, the difference between the two groups was statistically significant (P< 0.05). The expression of EZH2 in the cytoplasm of prostate cancers was significantly higher than that in the prostate hyperplasias (P< 0.01). There was little correlation of carcinomas for EZH2 expression with preoperative serum PSA level, preoperative serum cPSA level, patient age, Gleason grading, and clinical stage (P> 0.05). There was notable negative correlation of staining of prostate carcinomas between EZH2 and PTEN (rs=-0.373, P< 0.01).
Conclusions:
(1) The expression of EZH2 in prostate cancer was significantly higher than in benign prostatic hyperplasia, which might be involved in the formation of prostate cancers.
(2) EZH2 was expressed in the nucleus of prostate cancer cells, but also accompanied the cytoplasm expression of majority prostate cancers. EZH2 staining in benign prostatic hyperplasia showed weak in the nucleus, which cytoplasm was almost no expression. We speculated that high expression of EZH2 in the cytoplasm of prostate cancer was closely related with the occurrence of prostate cancers.
(3) We observed in the experiment that some of well-differentiated glands in prostate cancer were not stained by EZH2, while the surrounding irregular glands and diffuse tumor cells were stained better; Expression of the cytoplasm in prostate cancer cells correlated with Gleason grading. These suggested that EZH2 was related to tumor differentiation. To presume, expression of EZH2 related to the prognosis of prostatic carcinoma.
(4) EZH2 was a transcriptional inhibitory factor. There was notable negative of correlation staining of prostate carcinomas between EZH2 and PTEN. We suggested that PTEN might been one of be suppressed anti-oncogenes by EZH2. PTEN was decreased in prostate cancer and might promote together cancer occurrence with EZH2.
(5) The preoperative serum PSA and cPSA in prostate cancers were significantly higher than in patients with benign prostatic hyperplasia. They were all no significantly correlation with EZH2 in prostate cancers.They were as the commonly used indicator of prostate cancer for prostate cancer screening, differential diagnosis and postoperative review.
(6) There was no significantly correlation of carcinomas for EZH2 expression with preoperative serum PSA level, preoperative serum cPSA level, patient age and clinical stage.
引文
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