肺癌和前列腺癌骨转移血清蛋白质组学研究
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摘要
目的应用蛋白质组学双向荧光差异凝胶电泳和质谱技术寻找并鉴定肺癌骨转移患者与对照组肺癌无骨转移患者血清之间的差异表达蛋白,探讨肺癌骨转移患者血清中可能与肺癌骨转移发生、发展相关的蛋白质,以期寻找肺癌骨转移血清标志物。
方法收集男性肺癌伴骨转移、不伴骨转移各12例,女性肺癌伴骨转移、不伴骨转移各12例血清样本。同组血清等量混合,用除白蛋白试剂盒除去血清中的白蛋白,再经除盐浓缩后,将4组处理后的血清样品用不同的CyDye染料交叉标记后进行双向荧光差异凝胶电泳(2-D DIGE)。利用DeCyder软件分析,将肺癌伴骨转移与肺癌无骨转移比较的差异蛋白质点行基质辅助激光解析离子化飞行时间质谱(MALDI-TOF-MS)鉴定。
结果双向荧光差异凝胶电泳显示,肺癌骨转移组血清蛋白中有16个斑点与肺癌无骨转移组有显著差异。肺癌骨转移患者血清中11个蛋白质表达水平显著增加,5个蛋白质表达水平显著下降。5个差异蛋白点进行胶内原位酶解、肽质指纹图谱分析,成功得到了个4蛋白质肽质指纹图,并查询数据库初步鉴定了该4个蛋白质分别为RBP-TTR、结合珠蛋白(Hp)、S-亚硝基血红蛋白(SNO- Hb)、desArg141 alpha Hb。
结论双向荧光差异凝胶电泳结合质谱鉴定是血清差异蛋白质组学研究的可靠平台和有力工具。所鉴定出的蛋白质可能与肺癌骨转移的发生、发展有关,有助于肺癌骨转移发病机理的了解。
目的应用蛋白质组学双向凝胶电泳和质谱技术寻找并鉴定前列腺癌骨转移患者与对照组前列腺癌无骨转移患者血清之间的差异表达蛋白,探讨前列腺癌骨转移患者血清中可能与前列腺癌骨转移发生、发展相关的蛋白质,以期寻找前列腺癌骨转移血清标志物。
方法收集前列腺癌伴骨转移、不伴骨转移各5例血清样本。血清样品用除白蛋白试剂盒除去血清中的白蛋白后进行双向凝胶电泳, ImageMaster 2D Platinum软件分析,有意义的差异蛋白质点行基质辅助激光解析离子化飞行时间质谱(MALDI-TOF-MS)鉴定。
结果双向凝胶电泳显示,前列腺癌骨转移组血清蛋白中有15个斑点与前列腺癌无骨转移组有显著差异。前列腺癌骨转移患者血清中10个蛋白质表达水平显著增加,5个蛋白质表达水平显著下降。5个差异蛋白点进行胶内原位酶解,肽质量指纹图谱分析成功得到了3个蛋白质肽质量指纹图谱,并查询数据库初步鉴定了该3个蛋白质分别为锌α2糖蛋白、结合珠蛋白和载脂蛋白CⅢ。
结论双向凝胶电泳结合质谱鉴定是血清差异蛋白质组学研究的可靠平台和有力工具。所鉴定出的蛋白质与前列腺癌骨转移的发生、发展有关,可能是前列腺癌骨转移潜在的血清标志物。
Objective Using 2-D differential gel electrophoresis (2-D DIGE) and MS to screen serum biomarker candidates in lung cancer with bone metastases.
Methods serum samples from 12 male lung cancer patients with bone metastases,12 male lung cancer patients without bone metastases,12 female lung cancer patients with bone metastases and 12 female lung cancer patients without bone metastases were obtained. Serum samples of the same group were pooled and the most abundant protein albumin was depleted in order to enrich low-abundance proteins and proteins with low molecular weight. Concentrated and desalted samples were labeled with three different CyDyes including one internal standard, pooled from all the samples, and separated with 2-D DIGE in triplicate experiments. Biological variations of the protein expression level were analyzed with DeCyder software and evaluated for reproducibility and statistical significance. The differentially expressed protein spots in sera from lung cancer patients with bone metastases were analyzed by peptide-fingerprinting with matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF-MS).
Results A total of 11 protein spot-features were found to be significantly increased and 5 significantly decreased in lung cancer with bone metastases serum samples.The identified proteins included RBP-TTR complex that was decreased, haptoglobin, SNO-Hb, desArg141 alpha Hb that were increased in lung cancer with bone metastases serum samples.
Conclusions The combination of 2-D DIGE and mass spectrometry (MS) strategy is an ideal platform and powerful approach for differential proteomic analysis of human sera. 4 proteins might be involved in the process of lung cancer bone metastases and improve our understanding of the fundamental chang that contribute to the process of carcinogenesis and the formation of metastases in lung cancer with bone metastases..
Objective Using the two-dimensional gel electrophoresis (2-DE) and mass spectromet ry to screen serum biomarker candidates in prostate cancer with bone metastases.
Methods Serum samples from 5 prostate cancer patients with bone metastases,5 prostate cancer patients without bone metastases were obtained. The most abundant protein albumin in serum was depleted in order to enrich low-abundance proteins and proteins with low molecular weight. The samples were separated by two-dimensional electrophoresis (2-DE) and analyzed with ImageMaster 2D Platinum software.The differentially expressed protein spots in sera from prostate cancer patients with bone metastases were analyzed by peptide-fingerprinting with matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF-MS).
Results A total of 10 protein spot-features were found to be significantly increased and 5 significantly decreased in prostate cancer with bone metastases serum samples. The identified proteins included Zn-alpha2-glycoprotein(ZAG), haptoglobin and apolipop- roteinC-III that were increased in prostate cancer with bone metastases serum samples.
Conclusion The combination of 2-D and mass spectrometry (MS) strategy is an ideal platform and powerful approach for differential proteomic analysis of human sera. 3 proteins might be involved in the process of prostate cancer bone metastases and improve our understanding of the fundamental chang that contribute to the process of carcinogenesis and the formation of metastases in prostate cancer with bone metastases.The proteins might be applied as biomarkers for bone metastases from prostate cancer.
方法收集男性肺癌伴骨转移、不伴骨转移各12例,女性肺癌伴骨转移、不伴骨转移各12例血清样本。同组血清等量混合,用除白蛋白试剂盒除去血清中的白蛋白,再经除盐浓缩后,将4组处理后的血清样品用不同的CyDye染料交叉标记后进行双向荧光差异凝胶电泳(2-D DIGE)。利用DeCyder软件分析,将肺癌伴骨转移与肺癌无骨转移比较的差异蛋白质点行基质辅助激光解析离子化飞行时间质谱(MALDI-TOF-MS)鉴定。
结果双向荧光差异凝胶电泳显示,肺癌骨转移组血清蛋白中有16个斑点与肺癌无骨转移组有显著差异。肺癌骨转移患者血清中11个蛋白质表达水平显著增加,5个蛋白质表达水平显著下降。5个差异蛋白点进行胶内原位酶解、肽质指纹图谱分析,成功得到了个4蛋白质肽质指纹图,并查询数据库初步鉴定了该4个蛋白质分别为RBP-TTR、结合珠蛋白(Hp)、S-亚硝基血红蛋白(SNO- Hb)、desArg141 alpha Hb。
结论双向荧光差异凝胶电泳结合质谱鉴定是血清差异蛋白质组学研究的可靠平台和有力工具。所鉴定出的蛋白质可能与肺癌骨转移的发生、发展有关,有助于肺癌骨转移发病机理的了解。
目的应用蛋白质组学双向凝胶电泳和质谱技术寻找并鉴定前列腺癌骨转移患者与对照组前列腺癌无骨转移患者血清之间的差异表达蛋白,探讨前列腺癌骨转移患者血清中可能与前列腺癌骨转移发生、发展相关的蛋白质,以期寻找前列腺癌骨转移血清标志物。
方法收集前列腺癌伴骨转移、不伴骨转移各5例血清样本。血清样品用除白蛋白试剂盒除去血清中的白蛋白后进行双向凝胶电泳, ImageMaster 2D Platinum软件分析,有意义的差异蛋白质点行基质辅助激光解析离子化飞行时间质谱(MALDI-TOF-MS)鉴定。
结果双向凝胶电泳显示,前列腺癌骨转移组血清蛋白中有15个斑点与前列腺癌无骨转移组有显著差异。前列腺癌骨转移患者血清中10个蛋白质表达水平显著增加,5个蛋白质表达水平显著下降。5个差异蛋白点进行胶内原位酶解,肽质量指纹图谱分析成功得到了3个蛋白质肽质量指纹图谱,并查询数据库初步鉴定了该3个蛋白质分别为锌α2糖蛋白、结合珠蛋白和载脂蛋白CⅢ。
结论双向凝胶电泳结合质谱鉴定是血清差异蛋白质组学研究的可靠平台和有力工具。所鉴定出的蛋白质与前列腺癌骨转移的发生、发展有关,可能是前列腺癌骨转移潜在的血清标志物。
Objective Using 2-D differential gel electrophoresis (2-D DIGE) and MS to screen serum biomarker candidates in lung cancer with bone metastases.
Methods serum samples from 12 male lung cancer patients with bone metastases,12 male lung cancer patients without bone metastases,12 female lung cancer patients with bone metastases and 12 female lung cancer patients without bone metastases were obtained. Serum samples of the same group were pooled and the most abundant protein albumin was depleted in order to enrich low-abundance proteins and proteins with low molecular weight. Concentrated and desalted samples were labeled with three different CyDyes including one internal standard, pooled from all the samples, and separated with 2-D DIGE in triplicate experiments. Biological variations of the protein expression level were analyzed with DeCyder software and evaluated for reproducibility and statistical significance. The differentially expressed protein spots in sera from lung cancer patients with bone metastases were analyzed by peptide-fingerprinting with matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF-MS).
Results A total of 11 protein spot-features were found to be significantly increased and 5 significantly decreased in lung cancer with bone metastases serum samples.The identified proteins included RBP-TTR complex that was decreased, haptoglobin, SNO-Hb, desArg141 alpha Hb that were increased in lung cancer with bone metastases serum samples.
Conclusions The combination of 2-D DIGE and mass spectrometry (MS) strategy is an ideal platform and powerful approach for differential proteomic analysis of human sera. 4 proteins might be involved in the process of lung cancer bone metastases and improve our understanding of the fundamental chang that contribute to the process of carcinogenesis and the formation of metastases in lung cancer with bone metastases..
Objective Using the two-dimensional gel electrophoresis (2-DE) and mass spectromet ry to screen serum biomarker candidates in prostate cancer with bone metastases.
Methods Serum samples from 5 prostate cancer patients with bone metastases,5 prostate cancer patients without bone metastases were obtained. The most abundant protein albumin in serum was depleted in order to enrich low-abundance proteins and proteins with low molecular weight. The samples were separated by two-dimensional electrophoresis (2-DE) and analyzed with ImageMaster 2D Platinum software.The differentially expressed protein spots in sera from prostate cancer patients with bone metastases were analyzed by peptide-fingerprinting with matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF-MS).
Results A total of 10 protein spot-features were found to be significantly increased and 5 significantly decreased in prostate cancer with bone metastases serum samples. The identified proteins included Zn-alpha2-glycoprotein(ZAG), haptoglobin and apolipop- roteinC-III that were increased in prostate cancer with bone metastases serum samples.
Conclusion The combination of 2-D and mass spectrometry (MS) strategy is an ideal platform and powerful approach for differential proteomic analysis of human sera. 3 proteins might be involved in the process of prostate cancer bone metastases and improve our understanding of the fundamental chang that contribute to the process of carcinogenesis and the formation of metastases in prostate cancer with bone metastases.The proteins might be applied as biomarkers for bone metastases from prostate cancer.
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67. Diez-Itza I, Sanchez L. M, Allende MT, et al. Zn- 2-glycoprotein levels in breast cancer cytosols and correlation with clinical, histological, and biochemical parameters. Eur J Cancer, 1993, 29A: 1256-1260.
68. Hale LP, Price DT, Sanchez LM, et al. Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer. Clin Cancer Res ,2001,7:846-853.
69. Henshall SM , Horvath LG, Quinn DI, et al. Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy J Natl Cancer Inst ,2006, 98(19): 1420-1424.
70. Todorov PT, McDevitt TM, Meyer DJ, et al. Purification and characterization of a tumour lipid- mobilizing factor. Cancer Res ,1998, 58(11):2353–2358.
71. Hale LP, Price DT, Sanchez LM, et al. Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer. Clin Cancer Res, 2001,7(4):846-853.
72. Fujimura T, Shinohara Y, Tissot B, et al.Glycosylation status of haptoglobin in sera of patients with prostate cancer vs. benign prostate disease or normal subjects.Int J Cancer, 2008, 122(1):39-49.
73.王革非.肿瘤病人的代谢特点.中国实用外科杂志2002,22(11):690-692.
1 Coleman RE: The clinical use of bone resorption markers in patients with malignant bone disease. Cancer, 2002, 94: 2521-2533.
2 Cook RJ, Coleman R, Brown J, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res, 2006, 12(11 Pt 1):3361-3367.
3 Bajetta E, Martinetti A, Zilembo N, et al. Biological activity of anastrozole in postmenopausal patients with. advanced breast cancer: effects on estrogens and bone metabolism. Ann Oncol, 2002,13: 1059-1066.
4 Koopmans N, de Jong IJ, Breeuwsma AJ, et al. Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach. J Urol,2007,178(3 Pt 1):849-853.
5 Ebert W, Muley T, Herb KP, et al. Comparison of bone scintigraphy with bone markers in the diagnosis of bone metastasis in lung carcinoma patients. Anticancer Res, 2004, 24(5B):3193–3201.
6 Pollmann D, Siepmann S, Geppert R,et al. The amino-terminal propeptide (PINP) of type I collagen is a clinically valid indicator of bone turnover and extent of metastatic spread in osseous metastatic breast cancer. Anticancer Res,2007, 27(4A):1853-1862.
7 Jukkola A, Bloigu R, Holli K,et al. Postoperative PINP in serum reflects metastatic potential and poor survival in node-positive breast cancer. Anticancer Res, 2001, 21:2873–2876.
8 Diel IJ, Solomayer EF, Seibel MJ, et al. Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis. Clin Cancer Res,1999,5 (12) :3914-3919.
9 Liubimova NV, Bronnikov IIu, Robins SP, et al. The biochemical markers of bone remodeling in cancer patients with skeletal involvement. Vopr Onkol, 2000, 46(3):290-297.
10 Takahashi S. Evaluation of cancer-induced bone diseases by bone metabolic marker.Clin Calcium , 2006, 16(4):581- 590.
11 Ylisirnio S, Hoyhtya M, Makitaro R, et al. Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res, 2001,7(6):1633-1637.
12 Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol, 2005, 23(22): 4925-4935.
13 Chao TY, Yu JC, Ku CH, et al. Tartrate-resistant acid phosphatase 5b is a useful serum marker for extensive bone metastasis in breast cancer patients. Clin Cancer Res, 2005,11(2 Pt 1):544–550.
14 Capeller B, Caffier H, Sutterlin MW, et al. Evaluation of tartrate-resistant acid phosphatase (TRAP) 5b as serum marker of bone metastases in human breast cancer. Anticancer Res, 2003, 23(2A):1011–1015.
15 Hegele A, Wahl HG, Varga Z,et al. Biochemical markers of bone turnover in patients with localized and metastasized prostate cancer. BJU Int,2007,99(2):330-334.
16 Brown JM, Vessella RL, Kostenuik PJ, et al. Serum osteoprotegerin levels are increased in patients with advanced prostate cancer. Clin Cancer Res ,2001,7:2977–2983.
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68. Hale LP, Price DT, Sanchez LM, et al. Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer. Clin Cancer Res ,2001,7:846-853.
69. Henshall SM , Horvath LG, Quinn DI, et al. Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy J Natl Cancer Inst ,2006, 98(19): 1420-1424.
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73.王革非.肿瘤病人的代谢特点.中国实用外科杂志2002,22(11):690-692.
1 Coleman RE: The clinical use of bone resorption markers in patients with malignant bone disease. Cancer, 2002, 94: 2521-2533.
2 Cook RJ, Coleman R, Brown J, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res, 2006, 12(11 Pt 1):3361-3367.
3 Bajetta E, Martinetti A, Zilembo N, et al. Biological activity of anastrozole in postmenopausal patients with. advanced breast cancer: effects on estrogens and bone metabolism. Ann Oncol, 2002,13: 1059-1066.
4 Koopmans N, de Jong IJ, Breeuwsma AJ, et al. Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach. J Urol,2007,178(3 Pt 1):849-853.
5 Ebert W, Muley T, Herb KP, et al. Comparison of bone scintigraphy with bone markers in the diagnosis of bone metastasis in lung carcinoma patients. Anticancer Res, 2004, 24(5B):3193–3201.
6 Pollmann D, Siepmann S, Geppert R,et al. The amino-terminal propeptide (PINP) of type I collagen is a clinically valid indicator of bone turnover and extent of metastatic spread in osseous metastatic breast cancer. Anticancer Res,2007, 27(4A):1853-1862.
7 Jukkola A, Bloigu R, Holli K,et al. Postoperative PINP in serum reflects metastatic potential and poor survival in node-positive breast cancer. Anticancer Res, 2001, 21:2873–2876.
8 Diel IJ, Solomayer EF, Seibel MJ, et al. Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis. Clin Cancer Res,1999,5 (12) :3914-3919.
9 Liubimova NV, Bronnikov IIu, Robins SP, et al. The biochemical markers of bone remodeling in cancer patients with skeletal involvement. Vopr Onkol, 2000, 46(3):290-297.
10 Takahashi S. Evaluation of cancer-induced bone diseases by bone metabolic marker.Clin Calcium , 2006, 16(4):581- 590.
11 Ylisirnio S, Hoyhtya M, Makitaro R, et al. Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin Cancer Res, 2001,7(6):1633-1637.
12 Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol, 2005, 23(22): 4925-4935.
13 Chao TY, Yu JC, Ku CH, et al. Tartrate-resistant acid phosphatase 5b is a useful serum marker for extensive bone metastasis in breast cancer patients. Clin Cancer Res, 2005,11(2 Pt 1):544–550.
14 Capeller B, Caffier H, Sutterlin MW, et al. Evaluation of tartrate-resistant acid phosphatase (TRAP) 5b as serum marker of bone metastases in human breast cancer. Anticancer Res, 2003, 23(2A):1011–1015.
15 Hegele A, Wahl HG, Varga Z,et al. Biochemical markers of bone turnover in patients with localized and metastasized prostate cancer. BJU Int,2007,99(2):330-334.
16 Brown JM, Vessella RL, Kostenuik PJ, et al. Serum osteoprotegerin levels are increased in patients with advanced prostate cancer. Clin Cancer Res ,2001,7:2977–2983.
17 Eaton CL, Wells JM, Holen I, et al. Serum osteoprotegerin (OPG) levels are associated with disease progression and response to androgen ablation in patients with prostate cancer. Prostate, 2004, 59:304–310.
18 Jung K, Lein M, Stephan C,et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with metastatic spread: diagnostic and prognostics implications. Int J Cancer, 2004, 111(5):783–791.
19 Lipton A, Ali SM, Leitzel K, et al. Serum osteoprotegerin levels in healthy controls and cancer patients. Clin Cancer Res, 2002, 8(7):2306–2310.
20 Martinetti A, Ripamonti C, Miceli R, et al. Short-term effects of pamidronate on bone turnover: can bone markers be considered predictive of the analgesic response? Oncol Rep, 2007,17(6):1533-1540.
21 Body JJ, Facon T, Coleman RE,et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Cin Cancer Res,2006, 12(4):1221-1228.
22 Leeming DJ, Koizumi M, Byrjalsen I, et al. The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomarkers Prev, 2006, 15(1):32-38.
23 Grimaud E, Soubigou L, Couillaud S, et al. Receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis. Am J Pathol ,2003,163(5): 2021-2031.