卵巢上皮性癌差异蛋白的筛选及信号通路研究
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摘要
卵巢癌是女性生殖系统常见的恶性肿瘤之一,其发病率仅次于宫颈癌与子宫内膜癌位居第三。随着CA125联合经阴道超声筛查技术的应用,阳性诊断率仍仅为50%。迄今,卵巢癌仍为威胁女性健康的最主要的癌症,晚期的卵巢癌患者5年存活率仅为20%~30%。Pathway Array技术是一种具有高度敏感性和特异性的技术。该种方法用于卵巢癌差异表达蛋白的筛查尚未见相关报道。本论文通过Pathway Array技术筛查与卵巢癌发病相关的差异表达蛋白。目的:探索卵巢癌发生发展的信号转导机制,寻找用于卵巢癌早期诊断的生物学标记物及其分子治疗靶点。方法与结果:(1)体外实验:体外培养卵巢癌细胞和正常卵巢细胞,提取细胞总蛋白,用Pathway Array技术进行蛋白表达,用QUANTITY ONE分析软件进行差异蛋白表达谱分析,以卵巢癌细胞系SKOV3细胞为例与正常卵巢细胞系相比,6个蛋白表达水平有明显的升高:p-HER2/ErbB2、p-PDK1(Ser241)、p-Akt(Ser473)、TTF-1、ERK1/2和p-Stat3(Ser727)蛋白,4个蛋白表达水平有明显的降低:p-RB(Ser780)、p-c-Jun(Ser73)、Cdc25B和p-p53(Ser392)蛋白。(2)卵巢癌组织中差异表达蛋白的研究:在卵巢癌组织的高水平表达蛋白共12个,即p-Stat3 (Ser727)、p-PDK1 (Ser241)、p-Akt (Ser473)、p-cdc2 (Tyr15)、PCNA、Cdc2 p34、XIAP、E-cadherin、Cdk2、Mesothelin、p-p38 (pThr180/pTyr1 82)和P53蛋白;卵巢癌组织的低表达蛋白共9个,即ERK1/2、Cdc25C、Wee-1、cdc42、Bax、N-cadherin、α-tubulin、Vimentin和PTEN蛋白。(3)SKOV3细胞与卵巢癌组织的高水平表达蛋白有3个呈一致性高表达,即p-PDK1、p-Akt、p-Stat3;SKOV3细胞与卵巢癌组织的蛋白表达的差异性,显示在体肿瘤发生发展的复杂性,譬如,在SKOV3细胞p-p53的表达水平明显降低,而在卵巢癌组织中p-p53的表达水平则极显著地增高,是机体上调了野生型P53的表达,还是P53发生基因突变了需要进一步研究。对SKOV3细胞与卵巢癌组织中一致的高水平表达蛋白进行了免疫组织化学和Western Blot的验证,与Pathway array技术所获得的结果显示明显的一致性。(4)应用IPA系统分析21个差异表达蛋白相关的经典的信号通路和差异表达蛋白在信号传导中涉及的功能,得到与卵巢癌发生发展相关的信号通路网络。
结论:初步探讨卵巢癌发生发展的信号传导机制,为寻找新的有效提高卵巢癌早期诊断率的肿瘤标志物和基因治疗的靶点,提供了有益的线索和理论基础。
Epithelial ovarian cancer is the third common cancer in female gynecological malignancies, but the mortality rate of EOC is the first one among the female reproductive tract malignant tumors. The ovarian locates deep in the pelvis, there were not typical early symptoms of the disease or even no obvious symptoms, that is why early diagnosis rate of EOC is not high. Only about 20% patients were diagnosed in stage I, the other 2/3 of patients were diagnosed at stage III or IV. In the recent years, although rapid progress had been made in surgery and chemotherapy following surgery, the advanced EOC patients had poor prognosis, 5-year survival rate was only about 20%, while survival rate of stage I EOC was up to 80-90%. Therefore, the study of ovarian cancer pathogenesis, markers of early diagnosis and treatment methods is of great significance.
The progress of proteomics helps to provide a theoretical basis and solution to clarify the mechanism of disease and overcome the disease. By comparative proteomics research, the detect of differences from sick individual to the normal individuals, "specific disease-related proteins" could be found out, which can not only serve as markers for early diagnosis of disease, but also can be a molecular target for new drugs. Pathway Array technology systems choose some high-affinity antibodies to analyze over a thousand of proteins in a single sample, including the activated phosphorylated proteins and non-phosphorylated total proteins, to help to find signal transduction molecules changes in more comprehensive way. In Pathway Array technology, protein samples could be extracted from cell lines cultured in vitro and ultra-low temperature frozen tissue samples, then the proteins were separated by SDS-PAGE electrophoresis, transferred to NC membrane and then fixed the NC membrane in a Western blotting manifold that isolates 20 channels across the membrane, then add 600 ul of primary antibodies (diluted in blocking buffer) to each channel, each channel contains two to four antibodies, the molecular weight are significantly different from each other in the same channel, which benefits the access to the image. After hybridization, the NC membranes are analysed by Quantity One software Chemi XRS system to obtain images of different protein bands by chemiluminescence technology reflects the combination of the antibodies by specific proteins, and then by Chemi Doc system to make sure protein molecular weight corresponding to each phosphorylation proteins band or non-phosphorylated proteins band for protein characterization, and get relative expression volume of proteins by analysis of expression volume of each protein compared to the internal reference for quantitative comparison. NC membrane with the antibodies were cleaned by stripping buffer, and then another set of antibodies could be blotted. Phosphorylation antibodies are blotted first in order and then the non-phosphorylated antibodies were blotted. Blotting of non-phosphorylated antibodies can be repeated several times, 300-400 antibodies could be blotted in a single film. The advantages of pathway array technology include:①With pathway array technology, there are more specificity and accuracy in identifying the correct non-phosphorylated proteins and phosphorylated proteins than the traditional protein array technology and reverse protein array approach, only 80% to 90% of proteins detected by pathway array could be identified by traditional Western blot technique,②It is more sensitivity, the sensitivity can reach 1ng each belt when detected by chemiluminescence technology compared to traditional Western blot technique. It has repeatability. Therefore, this study used the following research pathway array technology.
Objective:To explore the pathogenesis of ovarian cancer to seek for sensitive specific biological markers for early diagnosis, looking for molecular therapeutic target for ovarian cancer, provide experimental basis and theoretical basis for early diagnosis and treatment of EOC.
Methods: (1)Research of differential proteomics of EOC were done through pathway array technology. Protein samples include ovarian cancer cell lines cultured in vitro and ultra-low temperature frozen tissue samples, then the proteins were separated by SDS-PAGE electrophoresis, transferred to NC membrane and then fixed the NC membrane with a Western blotting manifold that isolates 20 channels across the membrane, 2-4 kinds of antibodies which molecular weight differs from each other are blotted respectively in each channel, and western blotting were carried on as regular. Chemiluminescene exposure using Immun-StarTM HRP Peroxide Buffer/Immun-StarTM HRP Luminol Enhancer which is mixed together by the ratio of 1:1. Each membrane is evenly covered by 5 ml of the mixture. Capture imaging through one minute per exposure for 10 exposures after incubating with the mixture for 5 minutes. The NC membranes are analysed by Quantity One software Chemi XRS system to obtain images of different protein bands by chemiluminescence technology reflects the combination of the antibodies by specific proteins, and then by Chemi Doc system to make sure protein molecular weight corresponding to each phosphorylation proteins band or non-phosphorylated proteins band for protein characterization, and get relative expression volume of proteins by analysis of expression volume of each protein compared to the internal reference for quantitative comparison. In proteins from cultured cell lines, twice overexpression are defined significant difference while in proteins from tissues of EOC, SAM software are used to define significant difference. (2) Immunohistochemical staining and Western blotting technology were processed to clarify proteins over-expressed both in ovarian cancer tissue and ovarian cell line, which both further verified the results of pathway array.
Results and discussion:(1)Differential expressed proteins in ovarian cancer cell lines (SKOV3 cells compared with IOSE 386 cells as an example):①6 over-expressed proteins: p-HER2/ErbB2 (Tyr1221/1222), p-PDK1 (Ser241), p-Akt (Ser473), TTF-1, ERK1/2 and p-Stat3 (Ser727) protein;②4 less-expressed proteins:p-RB (Ser780), p-p53 (Ser392), pc-Jun (Ser73), Cdc25B proteins. (2) Differential expressed proteins in ovarian cancer tissues compared with normal ovarian tissues:①12 over-expressed proteins: p-Stat3, p-PDK1, p-cdc2, p-p38, p-Akt, XIAP, PCNA, cdc2p34, p53, Cdk2, Mesothelin, E-cadherin proteins;②9 less-expressed proteins: ERK, Cdc25C, Wee 1, N-cadherin,α-tubulin, Vimentin, cdc42, Bax, PTEN protein levels are significantly decreased. (3)The study also uses immunohistochemical staining and Western blotting technology, further confirmed p-Stat3, Stat3, p-Akt, AKT, p-PDK1 over-expressed in ovarian cancer tissue compared with normal ovarian tissue, which both further verified the protein pathway array results. This shows that in vivo and in vitro ovarian cancer have started the same signaling pathway, the associated proteins should be the most prospects. However, differences proteins in ovarian cancer also showed that the expression of cell adhesion related proteins Mesothelin increased (8.29 fold), E-cadherin expression was increased (2..59 fold), X linked inhibitor of apoptosis protein XIAP expression increased 6.39 fold, the tumor suppressor gene protein P53 expression increased 21.50 fold. As can be seen from the above data the incidence of ovarian cancer in vivo complexity of the body by environmental constraints, so we will focus on the level of expression of ovarian cancer protein further studies to reveal whether there is a significant development value. With immunohistochemistry and Western Blot verification: both in SKOV3 ovarian cancer cell lines and in ovarian tissues, it was consistent with the high level expression of proteins which validate the results obtained with the pathway array. (4) With IPA system,we got top canonical pathways and networks for the 21 proteins.
Conclusions: (1) Make up a new flat for screening of ovarian cancer by Pathway array technology, (2)12 kinds of differential expressed proteins in cell lines and 21 kinds of proteins in tissues were found by detected of 110 kinds of antibodies, (3) Proteins only expressed in tissue may have more significance for developing of ovarian cancer. (4)Preliminary revealed the signal transduction mechanism in the development of ovarian cancer by pathway array technology: PI3K/Akt pathway, JNK pathway, ERK pathway, p38 MAPK pathway, P53 pathways, cell cycle regulation disorders in the pathogenesis of ovarian cancer, shows the incidence of ovarian cancer involving multiple signal transduction pathways, (5) Akt, PDK1 could be markers for diagnosis.
结论:初步探讨卵巢癌发生发展的信号传导机制,为寻找新的有效提高卵巢癌早期诊断率的肿瘤标志物和基因治疗的靶点,提供了有益的线索和理论基础。
Epithelial ovarian cancer is the third common cancer in female gynecological malignancies, but the mortality rate of EOC is the first one among the female reproductive tract malignant tumors. The ovarian locates deep in the pelvis, there were not typical early symptoms of the disease or even no obvious symptoms, that is why early diagnosis rate of EOC is not high. Only about 20% patients were diagnosed in stage I, the other 2/3 of patients were diagnosed at stage III or IV. In the recent years, although rapid progress had been made in surgery and chemotherapy following surgery, the advanced EOC patients had poor prognosis, 5-year survival rate was only about 20%, while survival rate of stage I EOC was up to 80-90%. Therefore, the study of ovarian cancer pathogenesis, markers of early diagnosis and treatment methods is of great significance.
The progress of proteomics helps to provide a theoretical basis and solution to clarify the mechanism of disease and overcome the disease. By comparative proteomics research, the detect of differences from sick individual to the normal individuals, "specific disease-related proteins" could be found out, which can not only serve as markers for early diagnosis of disease, but also can be a molecular target for new drugs. Pathway Array technology systems choose some high-affinity antibodies to analyze over a thousand of proteins in a single sample, including the activated phosphorylated proteins and non-phosphorylated total proteins, to help to find signal transduction molecules changes in more comprehensive way. In Pathway Array technology, protein samples could be extracted from cell lines cultured in vitro and ultra-low temperature frozen tissue samples, then the proteins were separated by SDS-PAGE electrophoresis, transferred to NC membrane and then fixed the NC membrane in a Western blotting manifold that isolates 20 channels across the membrane, then add 600 ul of primary antibodies (diluted in blocking buffer) to each channel, each channel contains two to four antibodies, the molecular weight are significantly different from each other in the same channel, which benefits the access to the image. After hybridization, the NC membranes are analysed by Quantity One software Chemi XRS system to obtain images of different protein bands by chemiluminescence technology reflects the combination of the antibodies by specific proteins, and then by Chemi Doc system to make sure protein molecular weight corresponding to each phosphorylation proteins band or non-phosphorylated proteins band for protein characterization, and get relative expression volume of proteins by analysis of expression volume of each protein compared to the internal reference for quantitative comparison. NC membrane with the antibodies were cleaned by stripping buffer, and then another set of antibodies could be blotted. Phosphorylation antibodies are blotted first in order and then the non-phosphorylated antibodies were blotted. Blotting of non-phosphorylated antibodies can be repeated several times, 300-400 antibodies could be blotted in a single film. The advantages of pathway array technology include:①With pathway array technology, there are more specificity and accuracy in identifying the correct non-phosphorylated proteins and phosphorylated proteins than the traditional protein array technology and reverse protein array approach, only 80% to 90% of proteins detected by pathway array could be identified by traditional Western blot technique,②It is more sensitivity, the sensitivity can reach 1ng each belt when detected by chemiluminescence technology compared to traditional Western blot technique. It has repeatability. Therefore, this study used the following research pathway array technology.
Objective:To explore the pathogenesis of ovarian cancer to seek for sensitive specific biological markers for early diagnosis, looking for molecular therapeutic target for ovarian cancer, provide experimental basis and theoretical basis for early diagnosis and treatment of EOC.
Methods: (1)Research of differential proteomics of EOC were done through pathway array technology. Protein samples include ovarian cancer cell lines cultured in vitro and ultra-low temperature frozen tissue samples, then the proteins were separated by SDS-PAGE electrophoresis, transferred to NC membrane and then fixed the NC membrane with a Western blotting manifold that isolates 20 channels across the membrane, 2-4 kinds of antibodies which molecular weight differs from each other are blotted respectively in each channel, and western blotting were carried on as regular. Chemiluminescene exposure using Immun-StarTM HRP Peroxide Buffer/Immun-StarTM HRP Luminol Enhancer which is mixed together by the ratio of 1:1. Each membrane is evenly covered by 5 ml of the mixture. Capture imaging through one minute per exposure for 10 exposures after incubating with the mixture for 5 minutes. The NC membranes are analysed by Quantity One software Chemi XRS system to obtain images of different protein bands by chemiluminescence technology reflects the combination of the antibodies by specific proteins, and then by Chemi Doc system to make sure protein molecular weight corresponding to each phosphorylation proteins band or non-phosphorylated proteins band for protein characterization, and get relative expression volume of proteins by analysis of expression volume of each protein compared to the internal reference for quantitative comparison. In proteins from cultured cell lines, twice overexpression are defined significant difference while in proteins from tissues of EOC, SAM software are used to define significant difference. (2) Immunohistochemical staining and Western blotting technology were processed to clarify proteins over-expressed both in ovarian cancer tissue and ovarian cell line, which both further verified the results of pathway array.
Results and discussion:(1)Differential expressed proteins in ovarian cancer cell lines (SKOV3 cells compared with IOSE 386 cells as an example):①6 over-expressed proteins: p-HER2/ErbB2 (Tyr1221/1222), p-PDK1 (Ser241), p-Akt (Ser473), TTF-1, ERK1/2 and p-Stat3 (Ser727) protein;②4 less-expressed proteins:p-RB (Ser780), p-p53 (Ser392), pc-Jun (Ser73), Cdc25B proteins. (2) Differential expressed proteins in ovarian cancer tissues compared with normal ovarian tissues:①12 over-expressed proteins: p-Stat3, p-PDK1, p-cdc2, p-p38, p-Akt, XIAP, PCNA, cdc2p34, p53, Cdk2, Mesothelin, E-cadherin proteins;②9 less-expressed proteins: ERK, Cdc25C, Wee 1, N-cadherin,α-tubulin, Vimentin, cdc42, Bax, PTEN protein levels are significantly decreased. (3)The study also uses immunohistochemical staining and Western blotting technology, further confirmed p-Stat3, Stat3, p-Akt, AKT, p-PDK1 over-expressed in ovarian cancer tissue compared with normal ovarian tissue, which both further verified the protein pathway array results. This shows that in vivo and in vitro ovarian cancer have started the same signaling pathway, the associated proteins should be the most prospects. However, differences proteins in ovarian cancer also showed that the expression of cell adhesion related proteins Mesothelin increased (8.29 fold), E-cadherin expression was increased (2..59 fold), X linked inhibitor of apoptosis protein XIAP expression increased 6.39 fold, the tumor suppressor gene protein P53 expression increased 21.50 fold. As can be seen from the above data the incidence of ovarian cancer in vivo complexity of the body by environmental constraints, so we will focus on the level of expression of ovarian cancer protein further studies to reveal whether there is a significant development value. With immunohistochemistry and Western Blot verification: both in SKOV3 ovarian cancer cell lines and in ovarian tissues, it was consistent with the high level expression of proteins which validate the results obtained with the pathway array. (4) With IPA system,we got top canonical pathways and networks for the 21 proteins.
Conclusions: (1) Make up a new flat for screening of ovarian cancer by Pathway array technology, (2)12 kinds of differential expressed proteins in cell lines and 21 kinds of proteins in tissues were found by detected of 110 kinds of antibodies, (3) Proteins only expressed in tissue may have more significance for developing of ovarian cancer. (4)Preliminary revealed the signal transduction mechanism in the development of ovarian cancer by pathway array technology: PI3K/Akt pathway, JNK pathway, ERK pathway, p38 MAPK pathway, P53 pathways, cell cycle regulation disorders in the pathogenesis of ovarian cancer, shows the incidence of ovarian cancer involving multiple signal transduction pathways, (5) Akt, PDK1 could be markers for diagnosis.
引文
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