分泌蛋白质组学在肿瘤标志物中的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2017.03.003

摘要/Abstract

摘要： 在肿瘤发生、发展过程中,肿瘤细胞会分泌出大量蛋白质,而一些分泌蛋白已作为肿瘤标志物被用于肿瘤的临床检测与预后判断。随着蛋白质组学技术的快速发展,分泌蛋白质组学应运而生,并为肿瘤研究提供了新的思路与方法。现就分泌蛋白质组学在肿瘤标志物研究中的策略及进展做一综述,旨在为研究人员在肿瘤标志物发现及筛选方面提供借鉴。

关键词: 分泌蛋白, 分泌蛋白质组, 分泌蛋白质组学, 肿瘤标志物

Abstract: In the occurrence and development processes of tumor,a large number of proteins are secreted by tumor cells,and some of them are considered as tumor markers and used for clinical detection and prognosis. With the rapid development of proteomics techniques,secretomics is born at the right moment and provides new ideas and methods for tumor research. Now the strategy and the advance in the study of tumor markers by secretomics are reviewed,which may provide reference for the researchers in the discovery and screening of tumor markers.

Key words: secreted proteins, secretome, secretomics, tumor markers

余乐正, 柳凤娟, 吴正雨, 冉小强. 分泌蛋白质组学在肿瘤标志物中的研究进展[J]. 生物技术通报, 2017, 33(3): 12-21.

YU Le-zheng, LIU Feng-juan, WU Zheng-yu, RAN Xiao-qiang. Research Progress on Tumor Markers by Secretomics[J]. Biotechnology Bulletin, 2017, 33(3): 12-21.

参考文献

[1] Jemal A, Bray F, Center MM, et al. Global cancer statistics[J]. CA Cancer J Clin, 2011, 61（2）：69-90.
[2] 王凡羽, 刘刚, 郭玉. 蛋白质组学在肿瘤研究中的应用[J]. 基层医学论坛, 2013, 17（17）：2276-2277.
[3] Bendtsen JD, Jensen LJ, Blom N, et al. Feature-based prediction of non-classical and leaderless protein secretion[J]. Protein Eng Des Sel, 2004, 17（4）：349-356.
[4] Klee EW, Sosa CP. Computational classification of classically secreted proteins[J]. Drug Discov Today, 2007, 12（5-6）：234-240.
[5] Wilkins MR, Sanchez JC, Gooley AA, et al. Progress with proteome projects：why all proteins expressed by a genome should be identified and how to do it[J]. Biotechnol Genet Eng Rev, 1996, 13（1）：19-50.
[6] Tjalsma H, Bolhuis A, Jongbloed JD, et al. Signal peptide-dependent protein transport in Bacillus subtilis：a genome-based survey of the secretome[J]. Microbiol Mol Biol Rev, 2000, 64（3）：515-547.
[7] 邓孟垚, 曹亚. 血清分泌蛋白质组学在肿瘤中的研究进展[J]. 中国生物工程杂志, 2010, 30（11）：83-87.
[8] Karagiannis GS, Pavlou MP, Diamandis EP. Cancer secretomics reveal pathophysiological pathways in cancer molecular oncology[J]. Mol Oncol, 2010, 4（6）：496-510.
[9] 陈燕. 肿瘤标志物临床应用原则[J]. 医学检验与临床, 2006, 17（1）：1-2.
[10] Paul D, Kumar A, Gajbhiye A, et al. Mass spectrometry-based proteomics in molecular diagnostics：discovery of cancer biomarkers using tissue culture[J]. Biomed Res Int, 2013, 2013：783131.
[11] 黄立坤. 学看化验单（八）——怕得癌检查哪些指标[J]. 健康向导, 2012, 18（6）：4-5.
[12] Makridakis M, Vlahou A. Secretome proteomics for discovery of cancer biomarkers[J]. J Proteomics, 2010, 12：2291-2305.
[13] Pavlou MP, Diamandis EP. The cancer cell secretome：a good source for discovering biomarkers?[J]. J Proteomics, 2010, 73（10）：1896-1906.
[14] Anderson KS, Sibani S, Wallstrom G, et al. Protein microarray signature of autoantibody biomarkers for the early detection of breast cancer[J]. J Proteome Res, 2011, 10（1）：85-96.
[15] Lin LL, Huang HC, Juan HF. Discovery of biomarkers for gastric cancer：a proteomics approach[J]. J Proteomics, 2012, 75（11）：3081-3097.
[16] Paltridge JL, Belle L, Khew-Goodall Y. The secretome in cancer progression[J]. Biochim Biophys Acta, 2013, 1834（11）：2233-2241.
[17] Alvarez-Chaver P, Otero-Estévez O, Páez de la Cadena M, et al. Proteomics for discovery of candidate colorectal cancer biomarkers[J]. World J Gastroenterol, 2014, 14：3804-3824.
[18] Bhatnagar S, Katare DP, Jain SK. Serum-based protein biomarkers for detection of lung cancer[J]. Cent Eur J Biol, 2014, 9（4）：341-358.
[19] Schaaij-Visser TB, de Wit M, Lam SW, et al. The cancer secretome, current status and opportunities in the lung, breast and colorectal cancer context[J]. Biochim Biophys Acta, 2013, 1834（11）：2242-2258.
[20] Villarreal L, Méndez O, Salvans C, et al. Unconventional secretion is a major contributor of cancer cell line secretomes[J]. Mol Cell Proteomics, 2013, 12（5）：1046-1060.
[21] Hathout Y. Approaches to the study of the cell secretome[J]. Expert Rev Proteomics, 2007, 4（2）：239-248.
[22] 薛花, 来茂德. 肿瘤分泌蛋白质组研究进展[J]. 中华病理学杂志, 2007, 36（11）：777-780.
[23] 尹稳, 伏旭, 李平. 蛋白质组学的应用研究进展[J]. 生物技术通报, 2014（1）：32-38.
[24] Kočevar N, Hudler P, Komel R. The progress of proteomic approaches in searching for cancer biomarkers[J]. N Biotechnol, 2013, 30（3）：319-326.
[25] Guo S, Zou J, Wang G. Advances in the proteomic discovery of novel therapeutic targets in cancer[J]. Drug Des Devel Ther, 2013, 7（11）：1259-1271.
[26] Hudler P, Kočevar N, Komel R. Proteomic approaches in biomarker discovery：new perspectives in cancer diagnostics[J]. Sci World J, 2014, 2014：260348.
[27] 赵美玲. 蛋白芯片对肺癌肿瘤标志物的筛选和检测[D]. 保定：河北大学, 2007.
[28] Mukherjee P, Mani S. Methodologies to decipher the cell secretome[J]. Biochim Biophys Acta, 2013, 11：2226-2232.
[29] 王玮鹏, 苗芳芳, 武丹丹, 等. 蛋白质组学技术在细胞信号转导研究中的应用[J]. 生物技术通报, 2013（11）：46-50.
[30] 曾丽妮. CA153和CA19-9对恶性腹水的诊断价值[D]. 南宁：广西医科大学, 2009.
[31] 魏文杰, 秦涛, 胡伟, 等. 部分血清肿瘤标志物在临床诊断中的研究进展[J]. 安徽医药, 2009, 13（4）：355-357.
[32] 伍建蓉, 郑玲, 邬仁华, 等. 多种肿瘤标志物对肺癌转移的检测及预后评估[J]. 现代肿瘤医学, 2010, 6：1141-1142.
[33] 邢晓光. 血清胸苷激酶1水平变化对恶性肿瘤的诊断价值[J]. 山东医药, 2012, 52（23）：83-84.
[34] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65（2）：87-108.
[35] 赫捷, 陈万青. 2014中国肿瘤登记年报[M]. 北京：清华大学出版社, 2015.
[36] Yamashita R, Fujiwara Y, Ikari K, et al. Extracellular proteome of human hepatoma cell, HepG2 analyzed using two-dimensional liquid chromatography coupled with tandem mass spectrometry[J]. Mol Cell Biochem, 2007, 298（1-2）：83-92.
[37] Zinkin NT, Grall F, Bhaskar K, et al. Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease[J]. Clin Cancer Res, 2008, 14（2）：470-477.
[38] Sun S, Xu MZ, Poon RT et al. Circulating Lamin B1（LMNB1）biomarker detects early stages of liver cancer in patients[J]. J Proteome Res, 2010, 9（1）：70-78.
[39] Wu CC, Hsu CW, Chen CD, et al. Candidate serological biomarkers for cancer identified from the secretomes of 23 cancer cell lines and the human protein atlas[J]. Mol Cell Proteomics, 2010, 9（6）：1100-1117.
[40] 程华, 闫静辉. Glypican-3与肿瘤关系的研究进展[J]. 生物技术通报, 2010（2）：33-37.
[41] Wong KF, Luk JM. Discovery of lamin B1 and vimentin as circulating biomarkers for early hepatocellular carcinoma[J]. Methods Mol Biol, 2012, 909：295-310.
[42] Kim H, Kim K, Yu SJ, et al. Development of biomarkers for screening hepatocellular carcinoma using global data mining and multiple reaction monitoring[J]. PLoS One, 2013, 8（5）：e63468.
[43] Tessitore A, Gaggiano A, Cicciarelli G, et al. Serum biomarkers identification by mass spectrometry in high-mortality tumors[J]. Int J Proteomics, 2013, 2013（1）：125858.
[44] Mathew S, Ali A, Abdel-Hafiz H, et al. Biomarkers for virus-induced hepatocellular carcinoma（HCC）[J]. Infect Genet Evol, 2014, 26：327-339.
[45] Awan FM, Naz A, Obaid A, et al. Identification of circulating biomarker candidates for hepatocellular carcinoma（HCC）：an integrated prioritization approach[J]. PLoS One, 2015, 10（9）：e0138913.
[46] Chen G, Gharib TG, Huang CC, et al. Proteomic analysis of lung adenocarcinoma：identification of a highly expressed set of proteins in tumors[J]. Clin Cancer Res, 2002, 7：2298-2305.
[47] Lou X, Xiao T, Zhao K, et al. Cathepsin D is secreted from M-BE cells：its potential role as a biomarker of lung cancer[J]. J Proteome Res, 2007, 6（3）：1083-1092.
[48] Kim JE, Koo KH, Kim YH, et al. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model[J]. Exp Mol Med, 2008, 40（6）：709-720.
[49] 宋琳婧. 肺癌患者血清癌症促凝素临床意义的研究[D]. 昆明：昆明医学院, 2008.
[50] Planque C, Kulasingam V, Smith CR, et al. Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines[J]. Mol Cell Proteomics, 2009, 8（12）：2746-2758.
[51] Rodríguez-Piñeiro AM, Blanco-Prieto S, Sánchez-Otero N, et al. On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion[J]. J Proteomics, 2010, 73（8）：1511-1522.
[52] Luo X, Liu Y, Wang R, et al. A high-quality secretome of A549 cells aided the discovery of C4b-binding protein as a novel serum biomarker for non-small cell lung cancer[J]. J Proteomics, 2011, 74（4）：528-538.
[53] Yu CJ, Wang CL, Wang CI, et al. Comprehensive proteome analysis of malignant pleural effusion for lung cancer biomarker discovery by using multidimensional protein identification technology[J]. J Proteome Res, 2011, 10（10）：4671-4682.
[54] Na SS, Aldonza MB, Sung HJ, et al. Stanniocalcin-2（STC2）：A potential lung cancer biomarker promotes lung cancer metastasis and progression[J]. Biochim Biophys Acta, 2015, 1854（6）：668-676.
[55] Zhao R, Ji JG, Tong YP, et al. Use of serological proteomic methods to find biomarkers associated with breast cancer[J]. Proteomics, 2003, 3（4）：433-439.
[56] Mbeunkui F, Metge BJ, Shevde LA, et al. Identification of differentially secreted biomarkers using LC-MS/MS in isogenic cell lines representing a progression of breast cancer[J]. J Proteome Res, 2007, 6（8）：2993-3002.
[57] 吴策. 肺癌蛋白芯片检测系统在乳腺癌诊断中的价值[D]. 保定：河北大学, 2007.
[58] 王海霞. 乳腺癌阅读框架内噬菌体文库的构建[D]. 保定：河北大学, 2008.
[59] Kulasingam V, Zheng Y, Soosaipillai A, et al. Activated leukocyte cell adhesion molecule：a novel biomarker for breast cancer[J]. Int J Cancer, 2009, 125（1）：9-14.
[60] Lai TC, Chou HC, Chen YW, et al. Secretomic and proteomic analysis of potential breast cancer markers by two-dimensional differential gel electrophoresis[J]. J Proteome Res, 2010, 9（3）：1302-1322.
[61] McElwee JL, Mohanan S, Griffith OL, et al. Identification of PADI2 as a potential breast cancer biomarker and therapeutic target[J]. BMC Cancer, 2012, 12：e500.
[62] Jeon YR, Kim SY, Lee EJ, et al. Identification of annexin II as a novel secretory biomarker for breast cancer[J]. Proteomics, 2013, 13（21）：3145-3156.
[63] Tan AA, Mu AK, Kiew LV, et al. Comparative secretomic and N-glycoproteomic profiling in human MCF-7 breast cancer and HMEpC normal epithelial cell lines using a gel-based strategy[J]. Cancer Cell Int, 2014, 14（1）：120.
[64] Tan AA, Phang WM, Gopinath SC, et al. Revealing glycoproteins in the secretome of MCF-7 human breast cancer cells[J]. Biomed Res Int, 2015, 2015：453289.
[65] Zheng YX, Xu Y, Jerome P, et al. Protein chip array technology identify Pca-24, a potential protein marker in prostate cancer[J]. China Oncol, 2005, 15（3）：257-260.
[66] Sardana G, Marshall J, Diamandis EP. Discovery of candidate tumor markers for prostate cancer via proteomic analysis of cell culture-conditioned medium[J]. Clin Chem, 2007, 53（3）：429-437.
[67] Sardana G, Jung K, Stephan C, et al. Proteomic analysis of conditioned media from the PC3, LNCaP, and 22Rv1 prostate cancer cell lines：discovery and validation of candidate prostate cancer biomarkers[J]. J Proteome Res, 2008, 8：3329-3338.
[68] Zhao L, Lee BY, Brown DA, et al. Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling[J]. Cancer Res, 2009, 69（19）：7696-7703.
[69] Thoenes L, Hoehn M, Kashirin R, et al. In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy[J]. J Proteomics, 2010, 73（7）：1342-1354.
[70] Bijnsdorp IV, Geldof AA, Lavaei M, et al. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients[J]. J Extracell Vesicles, 2013, 2：22097.
[71] Liu Y, Chen J, Sethi A, et al. Glycoproteomic analysis of prostate cancer tissues by SWATH mass spectrometry discovers N-acylethanolamine acid amidase and protein tyrosine kinase 7 as signatures for tumor aggressiveness[J]. Mol Cell Proteomics, 2014, 13（7）：1753-1768.
[72] Yang YX, Sun XF, Cheng AL, et al. Increased expression of HSP27 linked to vincristine resistance in human gastric cancer cell line[J]. J Cancer Res Clin Oncol, 2009, 135（2）：181-189.
[73] Chong PK, Lee H, Zhou J, et al. ITIH3 is a potential biomarker for early detection of gastric cancer[J]. J Proteome Res, 2010, 9（7）：3671-3679.
[74] Deng L, Su T, Leng A, et al. Upregulation of soluble resistance-related calcium-binding protein（sorcin）in gastric cancer[J]. Med Oncol, 2010, 27（4）：1102.
[75] Loei H, Tan HT, Lim TK, et al. Mining the gastric cancer secretome：identification of GRN as a potential diagnostic marker for early gastric cancer[J]. J Proteome Res, 2012, 11（3）：1759-1772.
[76] Penno MA, Klingler-Hoffmann M, Brazzatti JA, et al. 2D-DIGE analysis of sera from transgenic mouse models reveals novel candidate protein biomarkers for human gastric cancer[J]. J Proteomics, 2012, 77：40-58.
[77] Marimuthu A, Subbannayya Y, Sahasrabuddhe NA, et al. SILAC-based quantitative proteomic analysis of gastric cancer secretome[J]. Proteomics Clin Appl, 2013, 7（5-6）：355-366.
[78] Wu JY, Cheng CC, Wang JY, et al. Discovery of tumor markers for gastric cancer by proteomics[J]. PLoS One, 2014, 9（1）：e84158.
[79] Wu CC, Chen HC, Chen SJ, et al. Identification of collapsin response mediator protein-2 as a potential marker of colorectal carcinoma by comparative analysis of cancer cell secretomes[J]. Proteomics, 2008, 8（2）：316-332.
[80] Ma Y, Peng J, Huang L, et al. Searching for serum tumor markers for colorectal cancer using a 2-D DIGE approach[J]. Electrophoresis, 2009, 30（15）：2591-2599.
[81] Liu W, Ma Y, Huang L, et al. Identification of HSP27 as a potential tumor marker for colorectal cancer by the two-dimensional polyac-rylamide gel electrophoresis[J]. Mol Biol Rep, 2010, 37（7）：3207-3216.
[82] Xue H, Lu B, Zhang J, et al. Identification of serum biomarkers for colorectal cancer metastasis using a differential secretome approach[J]. J Proteome Res, 2010, 9（1）：545-555.
[83] Lee H, Song M, Shin N, et al. Diagnostic significance of serum HMGB1 in colorectal carcinomas[J]. PLoS One, 2012, 7（4）：e34318.
[84] Shin J, Kim HJ, Kim G, et al. Discovery of melanotransferrin as a serological marker of colorectal cancer by secretome analysis and quantitative proteomics[J]. J Proteome Res, 2014, 13（11）：4919-4931.
[85] Chiang SF, Kan CY, Hsiao YC, et al. Bone marrow stromal antigen 2 is a novel plasma biomarker and prognosticator for colorectal carcinoma：a secretome-based verification study[J]. Dis Markers, 2015, 2015：874054.
[86] Lin Q, Lim HS, Lin HL, et al. Analysis of colorectal cancer glyco-secretome identifies laminin β-1（LAMB1）as a potential serological biomarker for colorectal cancer[J]. Proteomics, 2015, 15（22）：3905-3920.
[87] Cheng AL, Huang WG, Chen ZC, et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis[J]. Clin Cancer Res, 2008, 14（2）：435-445.
[88] Chang YH, Wu CC, Chang KP, et al. Cell secretome analysis using hollow fiber culture system leads to the discovery of CLIC1 protein as a novel plasma marker for nasopharyngeal carcinoma[J]. J Proteome Res, 2009, 8（12）：5465-5474.
[89] Chang KP, Wu CC, Chen HC, et al. Identification of candidate nasopharyngeal carcinoma serum biomarkers by cancer cell secretome and tissue transcriptome analysis：potential usage of cystatin A for predicting nodal stage and poor prognosis[J]. Proteomics, 2010, 10（14）：2644-2660.
[90] Tang CE, Tan T, Li C, et al. Identification of Galectin-1 as a novel biomarker in nasopharyngeal carcinoma by proteomic analysis[J]. Oncol Rep, 2010, 24（2）：495-500.
[91] Yang J, Zhou M, Zhao R, et al. Identification of candidate biomarkers for the early detection of nasopharyngeal carcinoma by quantitative proteomic analysis[J]. J Proteomics, 2014, 109：162-175.
[92] Nagler R, Bahar G, Shpitzer T, et al. Concomitant analysis of salivary tumor markers - a new diagnostic tool for oral cancer[J]. Clin Cancer Res, 2006, 12（13）：3979-3984.
[93] Weng LP, Wu CC, Hsu BL, et al. Secretome-based identification of Mac-2 binding protein as a potential oral cancer marker involved in cell growth and motility[J]. J Proteome Res, 2008, 7（9）：3765-3775.
[94] Hsu CW, Yu JS, Peng PH, et al. Secretome profiling of primary cells reveals that THBS2 is a salivary biomarker of oral cavity squamous cell carcinoma[J]. J Proteome Res, 2014, 13（11）：4796-4807.
[95] Chang KP, Lin SJ, Liu SC, et al. Low-molecular-mass secretome profiling identifies HMGA2 and MIF as prognostic biomarkers for oral cavity squamous cell carcinoma[J]. Sci Rep, 2015, 5：11689.
[96] Mathur SP, Mathur RS, Young RC. Cervical epidermal growth factor-receptor（EGF-R）and serum insulin-like growth factor II（IGF-II）levels are potential markers for cervical cancer[J]. Am J Reprod Immunol, 2000, 44（4）：222-230.
[97] Mathur SP, Mathur RS, Gray EA, et al. Serum vascular endothelial growth factor C（VEGF-C）as a specific biomarker for advanced cervical cancer：Relationship to insulin-like growth factor II（IGF-II）, IGF binding protein 3（IGF-BP3）and VEGF-A[corrected][J]. Gynecol Oncol, 2005, 98（3）：467-483.
[98] Lu D, Yang X, Jiang NY, et al. IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer[J]. Am J Surg Pathol, 2011, 35（11）：1638-1645.
[99] Wu D, Wang H, Li Z, et al. Cathepsin B may be a potential bioma-rker in cervical cancer[J]. Histol Histopathol, 2012, 1：79-87.
[100] Lin LH, Chang SJ, Hu RY, et al. Biomarker discovery for neuroendocrine cervical cancer[J]. Electrophoresis, 2014, 35（14）：2039-2045.
[101] Quillien V, Raoul JL, Laurent JF, et al. Comparison of Cyfra 21-1, TPA and SCC tumor markers in esophageal squamous cell carcinoma[J]. Oncol Rep, 1998, 5（6）：1561-1565.
[102] Gu ZD, Chen KN, Li M, et al. Clinical significance of matrix metalloproteinase-9 expression in esophageal squamous cell carcinoma[J]. World J Gastroenterol, 2005, 6：871-874.
[103] Liu CZ, Zhu PY, Shi MX, et al. Screening of serum proteome biomarker of esophageal squamous cell carcinoma by WCX2 protein chip[J]. China Oncol, 2007, 17（9）：701-705.
[104] 冯笑山, 单探幽, 高社干, 等. C-12多种肿瘤标志物蛋白芯片对食管癌转移及预后的研究[J]. 肿瘤防治研究, 2007, 34（9）：730-731.
[105] 单探幽, 冯笑山, 高社干, 等. 多种肿瘤标志物对食管癌转移的检测及预后评估[J]. 临床肿瘤学杂志, 2007, 12（7）：512-513.
[106] Zhu X, Ding M, Yu ML, et al. Identification of galectin-7 as a potential biomarker for esophageal squamous cell carcinoma by proteomic analysis[J]. BMC Cancer, 2010, 10：290.
[107] Yan SM, Han X, Han PJ, et al. SIRT3 is a novel prognostic biomarker for esophageal squamous cell carcinoma[J]. Med Oncol, 2014, 31（8）：103.
[108] Lin Q, Tan HT, Lim HS, et al. Sieving through the cancer secretome[J]. Biochim Biophys Acta, 2013, 1834（11）：2360-2371.
[109] Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonogr-aphy, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma：a systematic review[J]. Am J Gastroenterol. 2006, 101（3）：513-523.
[110] Hsieh SY, He JR, Yu MC, et al. Secreted ERBB3 isoforms are serum markers for early hepatoma in patients with chronic hepa-titis and cirrhosis[J]. J Proteome Res, 2011, 10（10）：4715-4724.
[111] 黄金桔. 非小细胞肺癌患者ADAM8的表达及临床意义研究[D]. 广州：广州医学院, 2009.
[112] Prensner JR, Rubin MA, Wei JT, et al. Beyond PSA：the next generation of prostate cancer biomarkers[J]. Sci Transl Med, 2012, 4（127）：127rv3.
[113] Pan YZ, Xiao XY, Zhao D, et al. Application of surface-enhanced laser desorption/ionization time-of-flight-based serum proteomic array technique for the early diagnosis of prostate cancer[J]. Asian J Androl, 2006, 8（1）：45-51.
[114] Chen WZ, Pang B, Yang B, et al. Differential proteome analysis of conditioned medium of BPH-1 and LNCaP cells[J]. Chin Med J（Engl）, 2011, 124（22）：3806-3809.
[115] 陈锋, 李为民, 王冬梅, 等. 联合检测血清肿瘤标志物在肺癌诊断中的价值[J]. 四川大学学报：医学版, 2008, 39（5）：832-835.
[116] 黄海燕. 抗结肠肿瘤相关抗原单克隆抗体的制备及鉴定[D]. 西安：第四军医大学, 2005.