绝经后妇女子宫内膜息肉中Survivin与COX-2的表达及临床意义
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摘要
【目的】:研究Survivin蛋白与COX-2蛋白在绝经后妇女子宫内膜息肉组织中的表达及二者之间的相关性和临床意义。【方法】:采用免疫组织化学方法检测Survivin蛋白和COX-2蛋白在40例绝经后妇女子宫内膜息肉组织、息肉患者子宫内膜组织及对照组子宫内膜组织中的表达,并初步探讨二者在子宫内膜息肉的发生发展中所起的作用和临床意义。【结果】: Survivin和COX-2在各组腺上皮细胞中均有不同程度的表达,且主要定位于胞浆。Survivin和COX-2蛋白在息肉腺上皮中的表达明显高于对照组与内膜组(P<0.05),而在对照组与内膜组间的表达差异无显著性(P>0.05)。Survivin蛋白和COX-2蛋白在息肉组腺上皮细胞中的表达成正相关。【结论】:COX-2和Survivin的高表达与子宫内膜息肉的发生发展及恶变密切相关,二者通过多种途径及机制参与子宫内膜息肉的发生发展。Survivin蛋白及COX-2蛋白在绝经后妇女子宫内膜息肉组织中表达成正相关,推测,EP发生过程中存在COX-2、Survivin两者协同作用,促进细胞生长,抑制细胞凋亡,促进新生血管形成,这可能是EP发生发展的机制之一。在COX-2蛋白和Survivin蛋白的共同表达中,可能存在着多种中介物质,通过多条途径,促进EP的形成和发展。通过探讨COX-2蛋白及Survivin蛋白在EP的发生发展中所起的重要作用,可能为临床治疗EP提供新的思路。如针对Srvivin的基因治疗及靶向性药物,诱导细胞凋亡;选择性COX-2抑制剂或者非特异性环氧化酶抑制剂的应用,从理论上二者均可治疗EP,并减少复发率,提高患者的生活质量。如能将上述理论应用于临床,可能开辟一条治疗EP的新途径。
Endometrial Polyps (EP) is a kind of common benign uterine cavity disorder. In recent years, with the improvement of transvaginal ultrasound and Hysteroscopy, the preoperative diagnosis of the disease was significantly increased. According to some reports ,the incidence rate of EP is about 24% to 25%, the rate of malignant transformation is about 1% to 1.6%. Especially in postmenopausal women, the rate of incidence and canceration are higher than those in premenopausal women, that has seriously affected the health of the women.At present, there are several hypothesis about the cause of EP : Traditionally, EP is a kind of reactive hyperplasia which relates to inflammation; It can also be thought that the EP is a kind of benign tumor of the endometrium; some scholars suspect that EP is a kind of precancerous lesions ,witch is similar to colorectal polyps; some consider that the pathogenesis of EP is related to endocrine disturbance in premenopausal women; Recent researches show that the occurrence of EP has genetic basis; In the field of molecular biology, many researches show that abnormal regulation of apoptosis plays a very important role in the development of EP, and a large number of experiments show that some factors that relates to apoptosis regulation, such as bcl-2, Ki-67, ras and PTEN ,take part in the development of EP. However, the exact etiology and pathogenesis have not been clear yet.
Survivin and COX-2 gene are new-found anti-apoptotic genes. Large number of studies show that they are highly expressed in majority benign and malignant tumors, and their high expression related to the stage and prognosis of tumors closely. Survivin gene is a kind of anti-apoptosis gene, it plays an important role in apoptosis and mitosis. Survivin gene expresses in majority of tumor cells and embryonic tissue, and doesn’t express in majority normal tissues, that shows that it may promote the genesis and development of tumor. Cyclooxygenase (COX) is the rate-limiting enzyme, and catalyzes the convertion of arachidonic acid to prostaglandins. Cyclooxygenase-2(COX-2) is one of the two isoenzyme of COX, which can be stimulated by a variety of factors both inside and outside the cells, and than its expression in tissues increases. Many scholars think that COX-2 can promote the development of tumors mainly by playing a role in stimulating cell growth , suppressing apoptosis, and promoting angiogenesis. Most studies show that Survivin and COX-2 express highly in the majority of benign and malignant tumors in gynecology, but the exact mechanism have not reached a consensus yet. And the expression and relationship of Survivin and COX-2 in endometrial polyp tissue has not been reported either. The experiment aim to study the expression and the relationship of Survivin and COX-2 in endometrial polyps in postmenopausal women, to research the pathogenesis of EP, so that we will provide theoretic basis for aetiology and mechanism of endometrial polyps and find a new way for its effective remedy.
Immunohistochemical method was used to detect the expression of Survivin and COX-2 protein in 30 cases of endometrium without endometrial polyps (control group), 40 cases of endometrial polyps (polyps group), and 40 cases of endometrium with endometrial polyps (endometrial group). All the subjects are postmenopausal women, and the time from their last menstrual period (LMP) to now are all more than one year. Concise statistical software 10.32 was performed to analyze the study data. Statistical significance was defined as P<0.05. Linear correlation analysis and Spearman rank correlation analysis were used to analyse the relationship between the two factors.
The results show that: Survivin and COX-2 protein was expressed in the epithelium of all the groups with different levels, and it mainly localized in the cytoplasm. The positive rate of Survivin protein in control group (6.67%), endometrial group (22.5%) and polyps group (67.5%) were gradually increased. The expression of Survivin protein was significantly higher in polyps group than that in control group and endometrial group (P <0.05). But the expression of Survivin in control group and endometrial group showed no significant difference (P>0.05). The positive rate of COX-2 protein in control group (6.67%), endometrial group (10%) and polyps group(27.5%) were gradually increased too. The expression in polyps group was significant higher than the other two (P <0.05). But the expression in control group and endometrial group showed no significant difference (P>0.05). The expression of Survivin and COX-2 protein in endometrial polyps was positively correlated.
We can draw the following conclusions: The high expression of Survivin and COX-2 protein in endometrial polyps may related to the genesis, the development and the malignant transformation of endometrial polyps. And we may presume that Survivin and COX-2 protein are closely involved in the development of endometrial polyps through various path and mechanisms. Moreover, we can speculate that Cox-2 and Survivin protein have cooperative effect in the genesis and development of endometrial polyps, such as stimulating cell growth, inhibiting apoptosis, and promoting angiogenesis synergistically, and this could be one mechanism of the formation and development of endometrial polyps. Through studying the expression, clinical significance and the correlation of COX-2 and Survivin protein in the endometrial polyps, we may provide new methods for the diagnosis and treatment of endometrial polyps. If we can develop new kinds of targeted drugs and gene therapy aiming directly at Survivin, and selective COX-2 inhibitors or non-specific inhibitors of the cyclooxygenase with lower side effects, both of which can cure the endometrial polyps effectively,reduce the relapse rate and improve the quality of life, theoretically.If the above theory can be applied in clinical therapy, it may open up a new way for the treatment of endometrial polyps.
Endometrial Polyps (EP) is a kind of common benign uterine cavity disorder. In recent years, with the improvement of transvaginal ultrasound and Hysteroscopy, the preoperative diagnosis of the disease was significantly increased. According to some reports ,the incidence rate of EP is about 24% to 25%, the rate of malignant transformation is about 1% to 1.6%. Especially in postmenopausal women, the rate of incidence and canceration are higher than those in premenopausal women, that has seriously affected the health of the women.At present, there are several hypothesis about the cause of EP : Traditionally, EP is a kind of reactive hyperplasia which relates to inflammation; It can also be thought that the EP is a kind of benign tumor of the endometrium; some scholars suspect that EP is a kind of precancerous lesions ,witch is similar to colorectal polyps; some consider that the pathogenesis of EP is related to endocrine disturbance in premenopausal women; Recent researches show that the occurrence of EP has genetic basis; In the field of molecular biology, many researches show that abnormal regulation of apoptosis plays a very important role in the development of EP, and a large number of experiments show that some factors that relates to apoptosis regulation, such as bcl-2, Ki-67, ras and PTEN ,take part in the development of EP. However, the exact etiology and pathogenesis have not been clear yet.
Survivin and COX-2 gene are new-found anti-apoptotic genes. Large number of studies show that they are highly expressed in majority benign and malignant tumors, and their high expression related to the stage and prognosis of tumors closely. Survivin gene is a kind of anti-apoptosis gene, it plays an important role in apoptosis and mitosis. Survivin gene expresses in majority of tumor cells and embryonic tissue, and doesn’t express in majority normal tissues, that shows that it may promote the genesis and development of tumor. Cyclooxygenase (COX) is the rate-limiting enzyme, and catalyzes the convertion of arachidonic acid to prostaglandins. Cyclooxygenase-2(COX-2) is one of the two isoenzyme of COX, which can be stimulated by a variety of factors both inside and outside the cells, and than its expression in tissues increases. Many scholars think that COX-2 can promote the development of tumors mainly by playing a role in stimulating cell growth , suppressing apoptosis, and promoting angiogenesis. Most studies show that Survivin and COX-2 express highly in the majority of benign and malignant tumors in gynecology, but the exact mechanism have not reached a consensus yet. And the expression and relationship of Survivin and COX-2 in endometrial polyp tissue has not been reported either. The experiment aim to study the expression and the relationship of Survivin and COX-2 in endometrial polyps in postmenopausal women, to research the pathogenesis of EP, so that we will provide theoretic basis for aetiology and mechanism of endometrial polyps and find a new way for its effective remedy.
Immunohistochemical method was used to detect the expression of Survivin and COX-2 protein in 30 cases of endometrium without endometrial polyps (control group), 40 cases of endometrial polyps (polyps group), and 40 cases of endometrium with endometrial polyps (endometrial group). All the subjects are postmenopausal women, and the time from their last menstrual period (LMP) to now are all more than one year. Concise statistical software 10.32 was performed to analyze the study data. Statistical significance was defined as P<0.05. Linear correlation analysis and Spearman rank correlation analysis were used to analyse the relationship between the two factors.
The results show that: Survivin and COX-2 protein was expressed in the epithelium of all the groups with different levels, and it mainly localized in the cytoplasm. The positive rate of Survivin protein in control group (6.67%), endometrial group (22.5%) and polyps group (67.5%) were gradually increased. The expression of Survivin protein was significantly higher in polyps group than that in control group and endometrial group (P <0.05). But the expression of Survivin in control group and endometrial group showed no significant difference (P>0.05). The positive rate of COX-2 protein in control group (6.67%), endometrial group (10%) and polyps group(27.5%) were gradually increased too. The expression in polyps group was significant higher than the other two (P <0.05). But the expression in control group and endometrial group showed no significant difference (P>0.05). The expression of Survivin and COX-2 protein in endometrial polyps was positively correlated.
We can draw the following conclusions: The high expression of Survivin and COX-2 protein in endometrial polyps may related to the genesis, the development and the malignant transformation of endometrial polyps. And we may presume that Survivin and COX-2 protein are closely involved in the development of endometrial polyps through various path and mechanisms. Moreover, we can speculate that Cox-2 and Survivin protein have cooperative effect in the genesis and development of endometrial polyps, such as stimulating cell growth, inhibiting apoptosis, and promoting angiogenesis synergistically, and this could be one mechanism of the formation and development of endometrial polyps. Through studying the expression, clinical significance and the correlation of COX-2 and Survivin protein in the endometrial polyps, we may provide new methods for the diagnosis and treatment of endometrial polyps. If we can develop new kinds of targeted drugs and gene therapy aiming directly at Survivin, and selective COX-2 inhibitors or non-specific inhibitors of the cyclooxygenase with lower side effects, both of which can cure the endometrial polyps effectively,reduce the relapse rate and improve the quality of life, theoretically.If the above theory can be applied in clinical therapy, it may open up a new way for the treatment of endometrial polyps.
引文
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2 Clark TJ ,Khan KS,Gupta JK.Current practice for the treatment of benign intrauterine polyps:a national questionaire survey of consultant gynaecologists in UK.Eur J Obstet Gynecol Reprod Biol ,2002,103(1):65-67.
3 夏恩兰,主编.妇科内镜学.北京:人民卫生出版社,2001.558-560.
4 赵君宇,张振玉等。Survivin 在胃癌中的表达及其与 COX-2 相关性的研究。中国癌症杂志,2004,14(1),15-18.
5 金玉,林连捷等。大肠癌组织中 Survivin 和 COX-2 表达的相关性。世界华人消化杂志,2004,12(5),1218-1220.
6 Nasu S,Yagihashi A,Izawa A,et al.Survivin mRNA expression in patiens with breast cancer.Anticancer Res,2002,22(3):1839-1843.
7 Span PN,Sweep Fc,Wiegerinck ET,et al.Survivin is an independent prognostic marker for risk stratification of breast cancer patients.Clin Chem,2004,50(11):1986-1993.
8 Asanuma K,Moriai R,Yaijima T,et al.Survivin as a radio resistance factor in pancreatic cancer.Jpn J Cancer Res,2000,91(11):1204-1209.
9 Ikeguchi M,Liu J,Kaibara N. Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment . Apoptosis,2002,7(1):23- 29.
10 Ambrosini G, Adida C,Alteri DC.A novel anti-apotosis gene ,Surviving,express in cancer and lymphoma[J].Nature Med,1997,(8):917-921.
11 Dannenberg AJ, Altorki NK, Boyle JO, et al. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer[J].Lancet Oncol, 2001,2(9):544-551.
12 Gebauer G, Hafner A,Siebzehnrubl E, Lang N.Role of hysteroscopy in detection and extraction of endometrialpolyps:results of a prospective study[J].Am J Obstet Gynecol,2002,186:1104.
13 Tjarks M, Van Voorhis BJ.Treatment of endometrial polyps [J].Obstet Gynecol, 2000, 96:886-889.
14 Conway EM, Pollefeyt S, Comelissen J, et al.Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions [J].Blood,2000,95(4):1435-1442.
15 Chao JI,Kuo PC,Hsu TS.Down-regulation of survivin in nitric oxide induced cell growth inhibition and apoptosis of the human lung carcinoma cells[J].J Biol Chem,2004,279(19):20267-20276.
16 Jin Y,Wei Y,Xiong L,et al.Differential regulation of survivin by p53 contributes to cell cycle dependent apoptosis[J].Cell Res,2005,15(5):361-370.
17 Suzuki A,Hayashida M,Ito T,et al.survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16(INK4a) and Cdk2/cyclin E complex activation[J].Oncogene,2000,19(29):3225-3234.
18 Hattori M,Sakamoto H,Satoh k,et al.DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CPG sites in the promoter region of C-erbB-2 and surviving genes.Cancer Lett, 2001, 169(2) : 155-164.
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