卵巢上皮性肿瘤组织中Maspin、p27和b-FGF的表达及意义
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摘要
卵巢恶性肿瘤(ovarian cancer)是女性生殖系统三大恶性肿瘤之一,其发病率占女性恶性肿瘤的2.4%-5.6%,近年来呈上升趋势。上皮性卵巢癌(epithelial ovarian cancer, EOC)起源于卵巢表面生发上皮,其主要生物学特征为浸润及转移,确切发病机制尚不清楚。卵巢肿瘤患者约70%在诊断时已为晚期,死亡率居女性生殖系统恶性肿瘤首位,其原因主要是临床上缺乏能够在早期检测卵巢癌的具有特异性及敏感性高的分子生物学标记物,因此,从基因水平对卵巢癌进行深入的研究,探讨其基因水平的发病机制,将对其早期诊断、尽早治疗和早期采取预防措施起到重要的作用。
癌症的发生、发展通常与细胞的增殖过度及凋亡不足有关。乳腺丝氨酸蛋白酶抑制剂(mammary serpin, Maspin)属于丝氨酸蛋白酶抑制剂(serpin)超家族,在人体内参与了多种生理学效应,主要表现为：增加细胞黏附能力,抑制肿瘤细胞的运动和迁移；抵抗血管新生；促进细胞凋亡,从而抑制肿瘤转移,在肿瘤发生进展中起到一定的作用。
细胞周期调控的失常与肿瘤的形成密切相关。p27是一种多功能细胞周期素依赖激酶抑制因子(cyclin dependent kinase inhibitor, CDKI),主要通过阻止细胞周期G0/G1期至S期的转换,从而抑制细胞周期进程,进而阻止细胞的增殖和肿瘤的形成。
碱性成纤维细胞生长因子(basic fibroblast growth factor, b-FGF)是成纤维细胞生长因子(Fibroblast Growth Factors, FGFs)家族中的一员,b-FGF广泛分布于中胚层和神经外胚层来源的多种组织和器官,也存在于肿瘤组织中,它具有促进细胞增殖、分化、迁移等多种生物学效应,并参与血管重塑、骨骼形成、神经发育、肿瘤代谢等生理和病理过程。
目的
本研究采用RT-PCR (reverse transcription polymerase chain reaction)法检测Maspin mRNA、p27 mRNA与b-FGF mRNA在正常及良性、恶性卵巢组织中的表达情况并分析三者相关性。阐明三者的表达与上皮性卵巢癌的生物学行为之间的相关性。在基因转录水平探讨细胞生长因子与抑癌基因在卵巢癌的发生发展中的作用。
材料与方法
1材料
收集郑州大学第一、第三附属医院2007年10月～2009年5月行手术切除的卵巢组织共79例。其中恶性上皮性卵巢肿瘤31例(浆液性16例,黏液性13例,子宫内膜样癌1例,透明细胞癌1例),良性上皮性卵巢肿瘤28例(浆液性12例,黏液性16例),正常卵巢组织20例,以上标本的诊断均经病理组织学检查确诊。所有病例术前均未接受放疗、化疗及免疫治疗。
2方法
采用RT-PCR法检测Maspin mRNA、p27 mRNA与b-FGF mRNA在正常及良性、恶性卵巢组织中的表达情况。
3结果判定
PCR产物经凝胶成像及分析系统扫描后,以β-actin为参照,求出其相对值。
4统计学分析
应用SPSS16.0统计学软件进行数据处理,连续型变量用(x±s)表示,采用独立样本t检验和单因素方差分析；正态分布资料的相关性检验采用Pearson积差相关分析,非正态分布资料的相关性检验采用Spearman秩相关分析,检验水准α=0.05。
结果
1 Maspin mRNA的表达
Maspin mRNA在恶性卵巢肿瘤中的相对灰度值低于良性卵巢肿瘤和正常卵巢。在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值低于Ⅰ、Ⅱ期；有淋巴结转移组中的表达低于无淋巴结转移组。
2 p27 mRNA的表达
p27 mRNA在恶性卵巢肿瘤中的相对灰度值低于良性卵巢肿瘤和正常卵巢,差异有统计学意义。在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值低于Ⅰ、Ⅱ期；有淋巴结转移组中的表达低于无淋巴结转移组。
3 b-FGF mRNA的表达
b-FGF mRNA在恶性卵巢肿瘤中的相对灰度值高于正常卵巢。b-FGF mRNA在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值高于Ⅰ、Ⅱ期；有淋巴结转移组中的表达高于无淋巴结转移组(P<0.05),高分化组与中、低分化组比较差异有统计学意义。
4相关性分析
三种mRNA在恶性卵巢组织中表达的相关性分析显示,Maspin mRNA和p27mRNA的表达呈正相关(r=0.688,P<0.001)；Maspin mRNA和b-FGF mRNA的表达水平呈负相关(r=-0.418,P=0.019)；p27 mRNA和b-FGF mRNA的表达成负相关(r=-0.434,P=0.015)。
结论
1 Maspin mRNA和p27 mRNA在卵巢肿瘤中低表达,b-FGF mRNA在卵巢肿瘤中高表达,表明其可能参与卵巢肿瘤的发生发展。
2 Maspin mRNA和p27 mRNA在卵巢癌有淋巴转移组及临床分期Ⅲ、Ⅳ期中低表达,其表达随临床分期升高而降低,表明Maspin mRNA和P27 mRNA表达水平的低下或缺失可能参与卵巢癌的发生发展。b-FGF mRNA在卵巢癌低分化组、有淋巴转移组及临床分期Ⅲ、Ⅳ期中高表达,其表达随临床分期升高而升高,表明其可能与卵巢癌的恶性程度相关。
3卵巢肿瘤中,Maspin mRNA、p27 mRNA和b-FGF mRNA具有高度相关性,表明三者可能存在某种联系,共同促进卵巢肿瘤的发生发展。
Ovarian cancer which is one of the most common malignant tumors of the female reproductive systems holds 2.4%-5.6% of the gynecologic malignancies, and its incidence rate is increased these years. Epithelial ovarian cancer is originated from the germinal epithelium of the ovary. Infiltrating and metastasis are the biocharacteristics of ovarian cancer, and the pathogenesis is not clear. Approximately 70% of patients with ovarian cancer are diagnosed only at advanced disease stages, and the mortality rate of the ovarian cancer is the first of genital organs malignant tumour. There are no specificity and high sensitivity biological markers which can detect the ovarian cancer in the early stage. Therefore, in order to solve the key point of the development of ovarian cancer, we should carry out deepgoing study from genes level, will conduce to the early diagnosis, the early treatment, and the protective measure of the ovarian cancer.
Cancer is a proliferative disease characterized by hyperproliferation and insufficient apoptosis. Mammary serpin belongs to serpin superfamily, and participates in many kinds of physiological effects in vivo, include increasing cell adhesion, inhibiting the movement and immigration of tumor cells, resisting the neogenesis of vessel, promoting apoptosis, thus inhibits neoplasm metastasis, and plays an important role in the tumor development.
Tumorigeness is closely correlated with the abnormal regulation of cell cycle. P27 is a multifunctional cyclin dependent kinase inhibitor. By preventing the inversion from G0/G1 stage to S stage of cell cycle, p27 can stop the progression of cell cycle. The cyclin-dependent kinase p27 plays an important role in the regulation of cell cycle progression, thereby the negative regulation of cell cycle is accomplished, and then p27 inhibites cell multiplication and tumorigeness.
Basic fibroblast growth factor is one of the FGFs, and is widly distributed in varied tissues and organs origined from mesoblastema and neural ectoderm, contains tumors. Basic fibroblast growth factor has a lot of biological effects, such as to promote proliferation, differentiation and metastasize, and participates physiological functions and pathological process, including the remodeling of blood vessels, skeletogeny, neural development and the metabolism of tumor.
Objective
In this study, using RT-PCR method we investigated the expression of Maspin mRNA, p27 mRNA and b-FGF mRNA in normal ovary, benign epithelial ovarian tumor and malignant ovarian tumor, and analyzed the relationship of Maspin mRNA, p27 mRNA and b-FGF mRNA, to interpret the correlation between their expression and the biological behaviour of epithelial ovarian cancer, and explore the role of cell growth factor and tumor suppressor gene in the development of ovarian cancer.
Methods
1 Sampling
79 cases accepted operation were selected from the first and the third affiliated hospital of Zhengzhou University from October 2007 and May 2005. The samplings include the normal ovary tissue (n=20)、benign epithelial ovarian tumor (n=28) and malignant ovarian tumor (n=31). No any drug was taken preoperatively, also no radiotherapy chemotherapy immunotherapy.
2 Method
RT-PCR was used to detect the expression of Maspin mRNA, p27 mRNA and b-FGF mRNA in normal ovary, benign epithelial ovarian tumor and malignant ovarian tumor.
3 Assessment
The gel imaging analytical system was used to scan the PCR production and exam the relative gray value of Maspin, p27 and b-FGF.
4 Statistic analysis
The data were recorded and analyzed by using SPSS16.0 package, and were signified by (x±s) for successive type variable, compared in two groups through independent sample t test, three groups through one way analysis of variance. The Pearson product-moment correlation analysis was used to test the data which is normal distribution, and the spearman rank correlation analysis was used to test the nonnormal distribution data.
Results
1 The expression of Maspin mRNA
The expression of Maspin mRNA was lower in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. Maspin mRNA were poorly expressed in stageⅢ,Ⅳ, lower than that in stageⅠ,Ⅱ, and they were lower in malignant ovarian tumor with lymphatic metastasis than that negativation.
2 The expression of p27 mRNA
The expression of p27 mRNA was lower in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. p27 mRNA were poorly expressed in stageⅢ,Ⅳ, lower than that in stageⅠ,Ⅱ, and they were lower in malignant ovarian tumor with lymphatic metastasis than that negativation.
3 The expression of b-FGF mRNA
The expression of b-FGF mRNA was higher in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. b-FGF mRNA was strongly expressed in stageⅢ,Ⅳ, higher than that in stageⅠ,Ⅱ, and it was higher in malignant ovarian tumor with lymphatic metastasis than that negativation, and the expression was higher in well differentiated group, compared with poorly differentiated group and moderately differentiated group.
4 Correlation
There was a direct correlation between the expression of Maspin mRNA and p27 mRNA (r=0.688, P<0.001), a negative correlation between the expression of Maspin mRNA and b-FGF mRNA in malignant ovarian tumor (r=-0.418,P=0.019), and there was a negative correlation between the expression of p27 mRNA and b-FGF mRNA (r=-0.434,P=0.015).
Conclusion
1 The expressions of Maspin mRNA and p27 mRNA in in malignant ovarian tumor were lower, and b-FGF mRNA was higher, which indicated that they might participate in the carcinogenesis and development of ovarian cancer.
2 The expressions of Maspin mRNA and p27 mRNA were poorly expressed in stage IV and malignant ovarian tumor with lymphatic metastasis, and their expression were lower with the higher clinical stage, which indicated that their downregulation or lost might participate in the carcinogenesis and development of ovarian tumor. The expressions of b-FGF mRNA were strongly expressed in stage IV and malignant ovarian tumor with lymphatic metastasis, and their expression were higher with the higher clinical stage, which showed that it might be correlation with the degree of malignancy of ovarian cancer.
3 There were direct correlations among the expression of Maspin mRNA、p27 mRNA and b-FGF mRNA, which showed that there were connections among them and they promote the the carcinogenesis and development of ovarian cancer together.
癌症的发生、发展通常与细胞的增殖过度及凋亡不足有关。乳腺丝氨酸蛋白酶抑制剂(mammary serpin, Maspin)属于丝氨酸蛋白酶抑制剂(serpin)超家族,在人体内参与了多种生理学效应,主要表现为：增加细胞黏附能力,抑制肿瘤细胞的运动和迁移；抵抗血管新生；促进细胞凋亡,从而抑制肿瘤转移,在肿瘤发生进展中起到一定的作用。
细胞周期调控的失常与肿瘤的形成密切相关。p27是一种多功能细胞周期素依赖激酶抑制因子(cyclin dependent kinase inhibitor, CDKI),主要通过阻止细胞周期G0/G1期至S期的转换,从而抑制细胞周期进程,进而阻止细胞的增殖和肿瘤的形成。
碱性成纤维细胞生长因子(basic fibroblast growth factor, b-FGF)是成纤维细胞生长因子(Fibroblast Growth Factors, FGFs)家族中的一员,b-FGF广泛分布于中胚层和神经外胚层来源的多种组织和器官,也存在于肿瘤组织中,它具有促进细胞增殖、分化、迁移等多种生物学效应,并参与血管重塑、骨骼形成、神经发育、肿瘤代谢等生理和病理过程。
目的
本研究采用RT-PCR (reverse transcription polymerase chain reaction)法检测Maspin mRNA、p27 mRNA与b-FGF mRNA在正常及良性、恶性卵巢组织中的表达情况并分析三者相关性。阐明三者的表达与上皮性卵巢癌的生物学行为之间的相关性。在基因转录水平探讨细胞生长因子与抑癌基因在卵巢癌的发生发展中的作用。
材料与方法
1材料
收集郑州大学第一、第三附属医院2007年10月～2009年5月行手术切除的卵巢组织共79例。其中恶性上皮性卵巢肿瘤31例(浆液性16例,黏液性13例,子宫内膜样癌1例,透明细胞癌1例),良性上皮性卵巢肿瘤28例(浆液性12例,黏液性16例),正常卵巢组织20例,以上标本的诊断均经病理组织学检查确诊。所有病例术前均未接受放疗、化疗及免疫治疗。
2方法
采用RT-PCR法检测Maspin mRNA、p27 mRNA与b-FGF mRNA在正常及良性、恶性卵巢组织中的表达情况。
3结果判定
PCR产物经凝胶成像及分析系统扫描后,以β-actin为参照,求出其相对值。
4统计学分析
应用SPSS16.0统计学软件进行数据处理,连续型变量用(x±s)表示,采用独立样本t检验和单因素方差分析；正态分布资料的相关性检验采用Pearson积差相关分析,非正态分布资料的相关性检验采用Spearman秩相关分析,检验水准α=0.05。
结果
1 Maspin mRNA的表达
Maspin mRNA在恶性卵巢肿瘤中的相对灰度值低于良性卵巢肿瘤和正常卵巢。在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值低于Ⅰ、Ⅱ期；有淋巴结转移组中的表达低于无淋巴结转移组。
2 p27 mRNA的表达
p27 mRNA在恶性卵巢肿瘤中的相对灰度值低于良性卵巢肿瘤和正常卵巢,差异有统计学意义。在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值低于Ⅰ、Ⅱ期；有淋巴结转移组中的表达低于无淋巴结转移组。
3 b-FGF mRNA的表达
b-FGF mRNA在恶性卵巢肿瘤中的相对灰度值高于正常卵巢。b-FGF mRNA在恶性卵巢组织中,临床分期Ⅲ、Ⅳ期的相对灰度值高于Ⅰ、Ⅱ期；有淋巴结转移组中的表达高于无淋巴结转移组(P<0.05),高分化组与中、低分化组比较差异有统计学意义。
4相关性分析
三种mRNA在恶性卵巢组织中表达的相关性分析显示,Maspin mRNA和p27mRNA的表达呈正相关(r=0.688,P<0.001)；Maspin mRNA和b-FGF mRNA的表达水平呈负相关(r=-0.418,P=0.019)；p27 mRNA和b-FGF mRNA的表达成负相关(r=-0.434,P=0.015)。
结论
1 Maspin mRNA和p27 mRNA在卵巢肿瘤中低表达,b-FGF mRNA在卵巢肿瘤中高表达,表明其可能参与卵巢肿瘤的发生发展。
2 Maspin mRNA和p27 mRNA在卵巢癌有淋巴转移组及临床分期Ⅲ、Ⅳ期中低表达,其表达随临床分期升高而降低,表明Maspin mRNA和P27 mRNA表达水平的低下或缺失可能参与卵巢癌的发生发展。b-FGF mRNA在卵巢癌低分化组、有淋巴转移组及临床分期Ⅲ、Ⅳ期中高表达,其表达随临床分期升高而升高,表明其可能与卵巢癌的恶性程度相关。
3卵巢肿瘤中,Maspin mRNA、p27 mRNA和b-FGF mRNA具有高度相关性,表明三者可能存在某种联系,共同促进卵巢肿瘤的发生发展。
Ovarian cancer which is one of the most common malignant tumors of the female reproductive systems holds 2.4%-5.6% of the gynecologic malignancies, and its incidence rate is increased these years. Epithelial ovarian cancer is originated from the germinal epithelium of the ovary. Infiltrating and metastasis are the biocharacteristics of ovarian cancer, and the pathogenesis is not clear. Approximately 70% of patients with ovarian cancer are diagnosed only at advanced disease stages, and the mortality rate of the ovarian cancer is the first of genital organs malignant tumour. There are no specificity and high sensitivity biological markers which can detect the ovarian cancer in the early stage. Therefore, in order to solve the key point of the development of ovarian cancer, we should carry out deepgoing study from genes level, will conduce to the early diagnosis, the early treatment, and the protective measure of the ovarian cancer.
Cancer is a proliferative disease characterized by hyperproliferation and insufficient apoptosis. Mammary serpin belongs to serpin superfamily, and participates in many kinds of physiological effects in vivo, include increasing cell adhesion, inhibiting the movement and immigration of tumor cells, resisting the neogenesis of vessel, promoting apoptosis, thus inhibits neoplasm metastasis, and plays an important role in the tumor development.
Tumorigeness is closely correlated with the abnormal regulation of cell cycle. P27 is a multifunctional cyclin dependent kinase inhibitor. By preventing the inversion from G0/G1 stage to S stage of cell cycle, p27 can stop the progression of cell cycle. The cyclin-dependent kinase p27 plays an important role in the regulation of cell cycle progression, thereby the negative regulation of cell cycle is accomplished, and then p27 inhibites cell multiplication and tumorigeness.
Basic fibroblast growth factor is one of the FGFs, and is widly distributed in varied tissues and organs origined from mesoblastema and neural ectoderm, contains tumors. Basic fibroblast growth factor has a lot of biological effects, such as to promote proliferation, differentiation and metastasize, and participates physiological functions and pathological process, including the remodeling of blood vessels, skeletogeny, neural development and the metabolism of tumor.
Objective
In this study, using RT-PCR method we investigated the expression of Maspin mRNA, p27 mRNA and b-FGF mRNA in normal ovary, benign epithelial ovarian tumor and malignant ovarian tumor, and analyzed the relationship of Maspin mRNA, p27 mRNA and b-FGF mRNA, to interpret the correlation between their expression and the biological behaviour of epithelial ovarian cancer, and explore the role of cell growth factor and tumor suppressor gene in the development of ovarian cancer.
Methods
1 Sampling
79 cases accepted operation were selected from the first and the third affiliated hospital of Zhengzhou University from October 2007 and May 2005. The samplings include the normal ovary tissue (n=20)、benign epithelial ovarian tumor (n=28) and malignant ovarian tumor (n=31). No any drug was taken preoperatively, also no radiotherapy chemotherapy immunotherapy.
2 Method
RT-PCR was used to detect the expression of Maspin mRNA, p27 mRNA and b-FGF mRNA in normal ovary, benign epithelial ovarian tumor and malignant ovarian tumor.
3 Assessment
The gel imaging analytical system was used to scan the PCR production and exam the relative gray value of Maspin, p27 and b-FGF.
4 Statistic analysis
The data were recorded and analyzed by using SPSS16.0 package, and were signified by (x±s) for successive type variable, compared in two groups through independent sample t test, three groups through one way analysis of variance. The Pearson product-moment correlation analysis was used to test the data which is normal distribution, and the spearman rank correlation analysis was used to test the nonnormal distribution data.
Results
1 The expression of Maspin mRNA
The expression of Maspin mRNA was lower in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. Maspin mRNA were poorly expressed in stageⅢ,Ⅳ, lower than that in stageⅠ,Ⅱ, and they were lower in malignant ovarian tumor with lymphatic metastasis than that negativation.
2 The expression of p27 mRNA
The expression of p27 mRNA was lower in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. p27 mRNA were poorly expressed in stageⅢ,Ⅳ, lower than that in stageⅠ,Ⅱ, and they were lower in malignant ovarian tumor with lymphatic metastasis than that negativation.
3 The expression of b-FGF mRNA
The expression of b-FGF mRNA was higher in malignant ovarian tumor than the benign epithelial ovarian tumor and the normal ovary. b-FGF mRNA was strongly expressed in stageⅢ,Ⅳ, higher than that in stageⅠ,Ⅱ, and it was higher in malignant ovarian tumor with lymphatic metastasis than that negativation, and the expression was higher in well differentiated group, compared with poorly differentiated group and moderately differentiated group.
4 Correlation
There was a direct correlation between the expression of Maspin mRNA and p27 mRNA (r=0.688, P<0.001), a negative correlation between the expression of Maspin mRNA and b-FGF mRNA in malignant ovarian tumor (r=-0.418,P=0.019), and there was a negative correlation between the expression of p27 mRNA and b-FGF mRNA (r=-0.434,P=0.015).
Conclusion
1 The expressions of Maspin mRNA and p27 mRNA in in malignant ovarian tumor were lower, and b-FGF mRNA was higher, which indicated that they might participate in the carcinogenesis and development of ovarian cancer.
2 The expressions of Maspin mRNA and p27 mRNA were poorly expressed in stage IV and malignant ovarian tumor with lymphatic metastasis, and their expression were lower with the higher clinical stage, which indicated that their downregulation or lost might participate in the carcinogenesis and development of ovarian tumor. The expressions of b-FGF mRNA were strongly expressed in stage IV and malignant ovarian tumor with lymphatic metastasis, and their expression were higher with the higher clinical stage, which showed that it might be correlation with the degree of malignancy of ovarian cancer.
3 There were direct correlations among the expression of Maspin mRNA、p27 mRNA and b-FGF mRNA, which showed that there were connections among them and they promote the the carcinogenesis and development of ovarian cancer together.
引文
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[14]Woenckhaus M, Bubendorf L, Dalquen P, et al. Nuclear and cytoplasmic Maspin expression in primary non-small cell lung cancer [J]. J Clin Pathol,2007,60 (5):483
[15]Ma Y, Peng ZL. Expression of maspin and its relation to tumor vascularization in epithelian ovarian cancer. Sichuan Da Xue Xue Bao Yi Xue Ban,2009,40(2):223-227
[16]Bolat F, Gumurdulu D, Erkanli S, et al. Maspin over-expression correlates with increased expression of vascular endothelial growth factors A, C, and D in human carcinoma [J]. Pathology Research and Practice,2008,204:379-387
[17]Sood AK, Fletcher MS, Gruman LM, et al. The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res,2002,8:2924-2932
[18]Klasa-Mazurkiewicz D, Narkiewicz J, Milczek T, et al. Maspin overexpression correlates with positive response to primary chemotherapy in ovarian cancer pations. Ggnecol Oncol, 2009, doi:10.1016/j. ygyno.2008.12.038
[19]Surowiak P, Matema V, Drag-Zalesinska M, et al. Maspin expression is characteristic for isplatin-sensitive ovarian cancer cells and for ovarian cancer cases of longer survival rates [J]. Int J Gynecol Pathol,2006,25(2):131-139
[20]Bryant P, Zheng Q, Pumiglia K. Focal Adhesion Kinase Controls Cellular Levels of P27/Kipl and p21/Cipl through Skp2-Dependent and Independent Mechanisms [J]. Mol Cell Biol,2006,26(11):4201-4213
[21]Dvorackova J, Uvirova M. A molecularly genetic determination of prognostic factors of the prostate cancer and their relationship to expression of protein p27kip1 [J]. Neoplasma,2007, 54(2):149-154
[22]Cho S, Kim JH, Back SH, et al. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase [J]. Mol Cell Biol,2005,25(4):1283-1297
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[1]乔丽娟,封全灵,赵静.上皮性卵巢癌中Maspin、p27表达的相关性及意义[J].中国妇幼保健,2010,25(10)：1382-1384
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[12]Schwarz S, Ettl T, Kleinsasser N, et al. Loss of Maspin expression is a negative prognostic factor in common salivary gland tumors [J]. Oral Oncol,2008,44(6):563-570
[13]Lee DY, Park CS, Kim HS, et al. Maspin and p53 protein expression in gastric adenocarcinoma and its clinical applications [J]. Appl Immunohistochem Mol Morphol, 2008,16(1):13
[14]Woenckhaus M, Bubendorf L, Dalquen P, et al. Nuclear and cytoplasmic Maspin expression in primary non-small cell lung cancer [J]. J Clin Pathol,2007,60 (5):483
[15]Ma Y, Peng ZL. Expression of maspin and its relation to tumor vascularization in epithelian ovarian cancer. Sichuan Da Xue Xue Bao Yi Xue Ban,2009,40(2):223-227
[16]Bolat F, Gumurdulu D, Erkanli S, et al. Maspin over-expression correlates with increased expression of vascular endothelial growth factors A, C, and D in human carcinoma [J]. Pathology Research and Practice,2008,204:379-387
[17]Sood AK, Fletcher MS, Gruman LM, et al. The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res,2002,8:2924-2932
[18]Klasa-Mazurkiewicz D, Narkiewicz J, Milczek T, et al. Maspin overexpression correlates with positive response to primary chemotherapy in ovarian cancer pations. Ggnecol Oncol, 2009, doi:10.1016/j. ygyno.2008.12.038
[19]Surowiak P, Matema V, Drag-Zalesinska M, et al. Maspin expression is characteristic for isplatin-sensitive ovarian cancer cells and for ovarian cancer cases of longer survival rates [J]. Int J Gynecol Pathol,2006,25(2):131-139
[20]Bryant P, Zheng Q, Pumiglia K. Focal Adhesion Kinase Controls Cellular Levels of P27/Kipl and p21/Cipl through Skp2-Dependent and Independent Mechanisms [J]. Mol Cell Biol,2006,26(11):4201-4213
[21]Dvorackova J, Uvirova M. A molecularly genetic determination of prognostic factors of the prostate cancer and their relationship to expression of protein p27kip1 [J]. Neoplasma,2007, 54(2):149-154
[22]Cho S, Kim JH, Back SH, et al. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase [J]. Mol Cell Biol,2005,25(4):1283-1297
[23]Chu I, Sun J, Arnaout A, et al. p27 phosphorylation by Src regulates inhibition of cyclinE-Cdk2 [J]. Cell,2007,128(2):281-294
[24]Erkanli S, Kayaselcuk F, Kuscu E, et al.Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium [J]. Int J Gynecol Cancer,2006,16(3): 1412-1418
[25]Schmider-Ross A, Pirsig O, Gottschalk E, et al. Cyclin-dependent kinase inhibitors CIP1(p21) and KIP1(p27) in ovarian cancer [J]. J Cancer Res Clin Oncol,2006,132 (3): 163-170
[26]Keikhaee MR, Kudo Y, Siriwardena S, et al. Skp2 expression is associated with down-regulation of P27 protein and cell proliferation in salivary adenoid cystic carcinoma [J].VirchowsArch,2007,450.(5):567-574
[27]Timmerbeul I, Garrett-Engele CM, Kossatz U, et al. Testing the importance of P27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer[J]. PNAS, 2006,103 (38):14009-14014
[28]Touriol C, Bornes S, Bonnal S, et al. Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons[J]. Biol Cell,2003,95:169-178
[29]Malkowski A, Sobolewski K, Jaworski S, et al.FGF binding by extracellular matrix components of Wharton's jelly[J].Acta Biochim Pol,2007,54(2):357-363
[30]Quarto N, Fong KD, Longaker MT. Gene profiling of cells expressing different FGF-2 forms. Gene,2005,356:49-68
[31]Hokari M, Matsuda Y, Wakai T, et al. Tumor suppressor carcinoem-bryonic antigen-related cell adhesion molecule 1 potentates the anchor-age-independent growth of human hepatoma HepG2 cells. Life Sci,2007,81:336-345
[32]Bailly K, Soulet F, Leroy D, et al. Uncoupling of cell proliferation basic fibroblast growth factor[J]. FASEB 2000,14:333-344
[33]Schlessinger J. Common and distinct elements in cellular signaling via EGF and FGF receptor 1 [J]. Science,2004,306:1506-1507
[34]Wenxue Z, Qianqian H, Hang L, et al. Improved neovascularization and wound repair by targeting human basic fibroblast growth factor (bFGF) to fibrin. J Mol Med,2008,86: 1127-1138
[35]Grothe C, Haastert K, Jungnickel J. Physiological function and putative therapeutic impact of the FGF-2 system in peripheral nerve regeneration-lessons from in vivo studies in mice and rats [J]. Brain Res Rev,2006,51:293-299
[36]Quarto N, Longaker MT. Molecular mechanisms of FGF-2 inhibitory activity in the osteogenic context of mouse adipose-derived stem cells (mASCs) [J]. Bone,2008,42: 1040-1052
[37]Rich JT, McAlinden A, Sandell L. FGF-2 and transcription factor expression in adipose stem cells [C].ASMB Meeting Abstracts/Matrix Biology,2006,25:S21-S22
[38]Natsuko K, Ayuko S, Kenji K, et al. Fibroblast growth factor-2 stimulates adipogenic differentiation of human adipose-derived stem cells [J]. Biochemical and Biophysical Research Communications,2007,359:239-244
[39]Mukdsi JH, DePaul AL, Petiti JP, et al. Pattern of FGF-2 isoform expression correlated with its biological action in experimental prolactinomas. Acta Neuropathol (Berl),2006,112: 491-501
[40]Zhong C, Xiaodong Z, Hongchao F, et al. The expressions and significance of Hpa and bFGF in oral squamous-cell carcinoma. Chinese-German Journal of Clinical Oncology, 2009,8(1):46-49
[41]Carmen B, Heather YL, JackLee J, et al. Immunohistochemical expression of basic fibroblast growth factor and fibroblast growth factor receptors 1 and 2 in the pathogenesis of lung cancer. Clin Cancer Res,2008,14(19):6014-6022
[42]Horstmann M, Merseburger AS, Heyde E, et al. Correlation of bFGF expression in renal cell cancer with clinical and histopathological features by tissue microarray analysis and measurement of serum levels. J Cancer Res Clin Oncol,2005,131:715-722
[43]Secord AA, Darcy KM, Hutson A, et al. Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer:a Gynecologic Oncology Group study. Gynecol Oncol,2007,106(1):221-232
[44]Zhang JJ, Wang B, Liu ZJ, et al. Effects of human peritoneal mesothelial cells on angiogenesis factor expression and secretion of ovarian carcinoma cells. Zhonghua Zhong Liu Za Zhi,2006,28(10):737-740
[45]Kruslin B. Apoptosis in pathologic prostatic processes. Acta Med Croatica,2009,63 (2): 49-52
[46]Uro-Coste E.2009 update in salivary gland tumoral pathology.Ann Pathol,2009,29 (4): 274-285
[47]Charpin C, Giusiano S, Secq V, et al. Quantitative immunocytochemical profile to predict early outcome of disease in triple-negative breast carcinomas. Int J Oncol,2009,34 (4): 983-993
[48]Kim YJ, Kim MA, Im SA, et al. Metastasis-associated protein S100A4 and p53 predict relapse in curatively resected stage Ⅲ and Ⅳ (MO) gastric cancer. Cancer Invest,2008, 26(2):152-158
[49]Shao LJ, Shi HY, Ayala G, et al. Haploinsufficiency of the maspin tumor suppressor gene leads to hyperplastic lesions in the prostate. Cancer Res,2008,68(13):5143-5151
[50]Li Z, Shi YH, Zhang M. Target expression of maspin in tumor vasculatures induces endothelial cell apoptosis [J]. Oncogene,2005,24(12):2008-2019
[51]Nickoloff BJ, LingenMW, Chang BD, et al. Tumor suppressor maspin is up-regulated during keratinocyte senescence, exerting a paracrine antiangiogenic activity. Cancer Res,2004, 64(9):2956-2961
[52]Rubatt JM, Darcy KM, Hutson A, et al. Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD 105, p53 status, and angiogenic marker expression:A Gynecologic Oncology Group study. Gynecol Oncol,2009,112(3):469-474
[53]Wang DL, Wang YF, Shi GS, et al. Correlation of hTERT expression to Maspin and bFGF expression and their significance in glioma. Chinese Journal of Cancer,2007,26(6): 601-606
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