骨桥蛋白在卵巢浆液性腺癌组织中的表达及其临床意义
|
摘要
背景与目的：卵巢癌是常见的女性生殖系统恶性肿瘤之一，其发病率居妇科恶性肿瘤的第三位，而病死率却位居妇科恶性肿瘤首位，其中卵巢浆液性腺癌是卵巢恶性肿瘤中最常见的病理类型。卵巢癌起病多隐匿，一旦出现症状多属于晚期（Ⅲ期～Ⅳ期），5年生存率不足30%，远低于早期卵巢癌的70%～90%。主要是由于缺乏有效的早期诊断方法、监测肿瘤复发及转移和判断预后的手段。因此，寻找有效的诊断指标来提高卵巢癌的早期诊断率、监测复发和判断预后能明显提高卵巢癌的5年生存率，降低死亡率，改善预后。骨桥蛋白(osteopontin, OPN)是一种分泌型磷酸化糖蛋白，近年来研究发现与肿瘤细胞生长、增殖、侵袭和转移密切相关。OPN在卵巢癌患者肿瘤组织中的表达水平显著高于卵巢良性肿瘤和正常卵巢组织，在卵巢癌的筛查、病情预测和预后判断中起重要作用，从而为卵巢癌的早期诊断、监测复发和预后判断提供了一个新的指标。
方法：采用免疫组织化学方法检测70例卵巢浆液性腺癌组织、22例卵巢浆液性腺瘤组织和15例正常卵巢组织中OPN的表达，根据各组数据进行统计学分析。
结果：1、OPN定位在细胞浆中，呈棕黄色，细胞核不着色。OPN在卵巢浆液性腺癌细胞中呈现明显的阳性表达，在卵巢浆液性腺瘤及正常卵巢细胞中呈弱阳性表达或阴性表达。2、OPN在卵巢浆液性腺癌组织中的阳性率为82.9%，在卵巢浆液性腺瘤组织中的阳性表达率为22.7%，OPN在卵巢浆液性腺癌组织中的阳性率显著高于卵巢浆液性腺瘤组织(P＜0.05)；OPN在正常卵巢组织中的阳性表达率为13.3%，OPN在卵巢浆液性癌组中的阳性表达率显著高于正常卵巢组(P<0.05)。3、OPN在Ⅰ期卵巢浆液性腺癌组织中的阳性率为60.0％，Ⅱ期为76.2％，Ⅲ期为96.2％，Ⅳ期为100.0％。OPN在Ⅲ期卵巢浆液性腺癌组织中的阳性率显著高于Ⅰ期（P＜0.05），OPN在Ⅳ期卵巢浆液性腺癌组织中的阳性率显著高于Ⅰ期（P＜0.05）。4、OPN在早期（Ⅰ期～Ⅱ期）卵巢浆液性腺癌组织中的阳性率为69.4％，晚期（Ⅲ期～Ⅳ期）为97.1％，OPN在晚期卵巢浆液性腺癌组织中的阳性率显著高于早期(P＜0.05)。5、OPN在高分化（G1）卵巢浆液性腺癌组织中的阳性率为74.1％，中分化（G2）为80.0％，低分化（G3）为95.7％，OPN在G3组卵巢浆液性腺癌组织中的阳性率显著高于G1组（P＜0.05）。6、OPN在有腹水的卵巢浆液性腺癌组织中的阳性率为95.2％，无腹水为64.3％，OPN在有腹水的卵巢浆液性腺癌组织中的阳性率显著高于无腹水(P＜0.05)。7、OPN在≤50岁卵巢浆液性腺癌组织中的阳性表达率为70.4％，＞50岁为90.7％，两者比较无显著差异(P＞0.05)。
结论：1、OPN在卵巢浆液性腺癌组织中的阳性率显著高于卵巢浆液性腺瘤组织及正常卵巢组织。2、OPN在卵巢浆液性腺癌患者组织中的表达与手术-病理分期和组织病理学分级有关。卵巢浆液性腺癌临床分期越晚、组织病理学分化越差，组织中的阳性表达率越高。3、OPN在有腹水组卵巢浆液性腺癌组织中的阳性表达率高于无腹水组。4、OPN在卵巢浆液性腺癌组织中的阳性表达率与患者年龄无关。5、OPN与卵巢浆液性腺癌的发生、发展、浸润及转移密切相关，可作为判定卵巢浆液性腺癌恶性程度及预测愈后的指标之一。
Background and objective：ovarian cancer is a common malignant tumorof the female reproductive system,its incidence rate is at third,but the mortalityrate is at first. The ovarian serous adenocarcinoma is the most commonhistologic type of malignant ovarian tumors.Ovarian cancer usually occult,once symptoms belong to more advanced (stage III～IV),the5year survivalrate is less than30%,well below the70%～90%of early ovarian cancer.Themain reason is due to the lack of effective tumor markers in detection of tumorrecurrence and metastasis,judging tumor prognosis.Therefore,we urgent needlooking for effective tumor marker to identify those high-risk patients withdistant metastasis and recurrence,giving them effective treatment.It canimprove the survival rate and the quality of life of patients with ovarian cancer.Osteopontin (OPN) is a secreted phosphorylated glycoprotein.The recentstudies have found it has close relationship with the growth, proliferation andinvasion, metastasis of tumor cell. It has important link between the expressionlevel of OPN in ovary malignant tumor tissue and tumor screening, diseaseforecast and prognosis.Thus,it offers a new index for malignant ovarian tumorearly diagnosis, monitoring recurrence and prognosis judgement.
Methods： The expressions of OPN in70cases of ovarian serousadenocarcinoma tissues,22cases of ovarian serous adenoma tissues, and15cases of normal ovarian tissues were detected by immunohistochemistrymethod.
Results：1.The positive expression rate of OPN was82.9%in ovarianserous adenocarcinoma tissues, The positive expression rate of OPN was22.7% in ovarian s serous adenoma tissues.The positive expression rate of OPN inovarian serous adenocarcinoma tissues is much higher than those in ovarianserous adenoma tissues(P<0.05).2.The positive expression rate of OPN innomal ovarian tissues is13.3%, The positive expression rate of OPN in ovarianserous adenocarcinoma tissues is much higher than those in nomal ovariantissues (P<0.05).3.The positive expression rates of OPN in stage Ⅰ，stage Ⅱ，stage Ⅲ，stage Ⅳ ovarian serous adenocarcinoma tumor tissueswas60.0％,was76.2％, was96.2％, and100.0％.The positive rate of OPN expression instageⅢ tumor tissues was dramatically higher than that in stage Ⅰ(P<0.05).4.The positive rate of OPN expression in stage Ⅳtumor tissues wasdramatically higher than that in stage Ⅰ(P<0.05). The positive expression ratesof OPN in early stage (stageⅠ～stageⅡ)ovarian serous adenocarcinomatumor tissues was69.4％, the late stage (stageⅢ～stageⅣ)is97.1%, Thepositive rate of OPN expression in late stage tumor tissues was dramaticallyhigher than that in early stage (P<0.05).5.The positive expression rates of OPNin G1，G2，and G3ovarian serous adenocarcinoma tumor tissues were74.1％,80.0％,100.0％, It was dramatically higher in G3tumor tissues than thatin G1(P<0.05).6.The positive expression rate of OPN in ovarian serousadenocarcinoma tumor with ascites tissues is95.2%, The positive expressionrate of OPN in ovarian serous adenocarcinoma tumor without ascites tissues is95.2%.The positive expression rate of OPN in ovarian serous adenocarcinomatumor with ascites tissues is dramatically higher than that in tumor tissueswithout ascites(P<0.05).7.The positive expression rate of OPN in age greaterthan50years of ovarian serous adenocarcinoma tumor tissues is90.7%, Thepositive expression rate of OPN in younger than or equal to50years of ovarianserous adenocarcinoma tumor tissues is70.4%.The positive rate of OPNexpression in younger than or equal to50years of ovarian serous is not dramatically higher than that in greater than50years(P＞0.05).
Conclusion：1.The positive expression rate of OPN in ovarian serouscystadenocarcinoma tissues is much higher than those in ovarian serouscystadenoma tissues and nomal ovarian tissues(P<0.05).2.There wascorrelation between the positive expression rate of OPN with pathologicalgrading and clinical stages.3.the later clinical stage and the worsedifferentiation of ovarian serous adenocarcinoma,the stronger positiveexpression rate of OPN.4.There was no relation between OPN and the age ofthe patients.5.Overexpression of OPN may has the relationship with thedevelopment,invasion and metastasis of ovarian serous adenocarcinom. Itspotential clinical significance can be used as a prognostic marker in ovariancancer patients.
方法：采用免疫组织化学方法检测70例卵巢浆液性腺癌组织、22例卵巢浆液性腺瘤组织和15例正常卵巢组织中OPN的表达，根据各组数据进行统计学分析。
结果：1、OPN定位在细胞浆中，呈棕黄色，细胞核不着色。OPN在卵巢浆液性腺癌细胞中呈现明显的阳性表达，在卵巢浆液性腺瘤及正常卵巢细胞中呈弱阳性表达或阴性表达。2、OPN在卵巢浆液性腺癌组织中的阳性率为82.9%，在卵巢浆液性腺瘤组织中的阳性表达率为22.7%，OPN在卵巢浆液性腺癌组织中的阳性率显著高于卵巢浆液性腺瘤组织(P＜0.05)；OPN在正常卵巢组织中的阳性表达率为13.3%，OPN在卵巢浆液性癌组中的阳性表达率显著高于正常卵巢组(P<0.05)。3、OPN在Ⅰ期卵巢浆液性腺癌组织中的阳性率为60.0％，Ⅱ期为76.2％，Ⅲ期为96.2％，Ⅳ期为100.0％。OPN在Ⅲ期卵巢浆液性腺癌组织中的阳性率显著高于Ⅰ期（P＜0.05），OPN在Ⅳ期卵巢浆液性腺癌组织中的阳性率显著高于Ⅰ期（P＜0.05）。4、OPN在早期（Ⅰ期～Ⅱ期）卵巢浆液性腺癌组织中的阳性率为69.4％，晚期（Ⅲ期～Ⅳ期）为97.1％，OPN在晚期卵巢浆液性腺癌组织中的阳性率显著高于早期(P＜0.05)。5、OPN在高分化（G1）卵巢浆液性腺癌组织中的阳性率为74.1％，中分化（G2）为80.0％，低分化（G3）为95.7％，OPN在G3组卵巢浆液性腺癌组织中的阳性率显著高于G1组（P＜0.05）。6、OPN在有腹水的卵巢浆液性腺癌组织中的阳性率为95.2％，无腹水为64.3％，OPN在有腹水的卵巢浆液性腺癌组织中的阳性率显著高于无腹水(P＜0.05)。7、OPN在≤50岁卵巢浆液性腺癌组织中的阳性表达率为70.4％，＞50岁为90.7％，两者比较无显著差异(P＞0.05)。
结论：1、OPN在卵巢浆液性腺癌组织中的阳性率显著高于卵巢浆液性腺瘤组织及正常卵巢组织。2、OPN在卵巢浆液性腺癌患者组织中的表达与手术-病理分期和组织病理学分级有关。卵巢浆液性腺癌临床分期越晚、组织病理学分化越差，组织中的阳性表达率越高。3、OPN在有腹水组卵巢浆液性腺癌组织中的阳性表达率高于无腹水组。4、OPN在卵巢浆液性腺癌组织中的阳性表达率与患者年龄无关。5、OPN与卵巢浆液性腺癌的发生、发展、浸润及转移密切相关，可作为判定卵巢浆液性腺癌恶性程度及预测愈后的指标之一。
Background and objective：ovarian cancer is a common malignant tumorof the female reproductive system,its incidence rate is at third,but the mortalityrate is at first. The ovarian serous adenocarcinoma is the most commonhistologic type of malignant ovarian tumors.Ovarian cancer usually occult,once symptoms belong to more advanced (stage III～IV),the5year survivalrate is less than30%,well below the70%～90%of early ovarian cancer.Themain reason is due to the lack of effective tumor markers in detection of tumorrecurrence and metastasis,judging tumor prognosis.Therefore,we urgent needlooking for effective tumor marker to identify those high-risk patients withdistant metastasis and recurrence,giving them effective treatment.It canimprove the survival rate and the quality of life of patients with ovarian cancer.Osteopontin (OPN) is a secreted phosphorylated glycoprotein.The recentstudies have found it has close relationship with the growth, proliferation andinvasion, metastasis of tumor cell. It has important link between the expressionlevel of OPN in ovary malignant tumor tissue and tumor screening, diseaseforecast and prognosis.Thus,it offers a new index for malignant ovarian tumorearly diagnosis, monitoring recurrence and prognosis judgement.
Methods： The expressions of OPN in70cases of ovarian serousadenocarcinoma tissues,22cases of ovarian serous adenoma tissues, and15cases of normal ovarian tissues were detected by immunohistochemistrymethod.
Results：1.The positive expression rate of OPN was82.9%in ovarianserous adenocarcinoma tissues, The positive expression rate of OPN was22.7% in ovarian s serous adenoma tissues.The positive expression rate of OPN inovarian serous adenocarcinoma tissues is much higher than those in ovarianserous adenoma tissues(P<0.05).2.The positive expression rate of OPN innomal ovarian tissues is13.3%, The positive expression rate of OPN in ovarianserous adenocarcinoma tissues is much higher than those in nomal ovariantissues (P<0.05).3.The positive expression rates of OPN in stage Ⅰ，stage Ⅱ，stage Ⅲ，stage Ⅳ ovarian serous adenocarcinoma tumor tissueswas60.0％,was76.2％, was96.2％, and100.0％.The positive rate of OPN expression instageⅢ tumor tissues was dramatically higher than that in stage Ⅰ(P<0.05).4.The positive rate of OPN expression in stage Ⅳtumor tissues wasdramatically higher than that in stage Ⅰ(P<0.05). The positive expression ratesof OPN in early stage (stageⅠ～stageⅡ)ovarian serous adenocarcinomatumor tissues was69.4％, the late stage (stageⅢ～stageⅣ)is97.1%, Thepositive rate of OPN expression in late stage tumor tissues was dramaticallyhigher than that in early stage (P<0.05).5.The positive expression rates of OPNin G1，G2，and G3ovarian serous adenocarcinoma tumor tissues were74.1％,80.0％,100.0％, It was dramatically higher in G3tumor tissues than thatin G1(P<0.05).6.The positive expression rate of OPN in ovarian serousadenocarcinoma tumor with ascites tissues is95.2%, The positive expressionrate of OPN in ovarian serous adenocarcinoma tumor without ascites tissues is95.2%.The positive expression rate of OPN in ovarian serous adenocarcinomatumor with ascites tissues is dramatically higher than that in tumor tissueswithout ascites(P<0.05).7.The positive expression rate of OPN in age greaterthan50years of ovarian serous adenocarcinoma tumor tissues is90.7%, Thepositive expression rate of OPN in younger than or equal to50years of ovarianserous adenocarcinoma tumor tissues is70.4%.The positive rate of OPNexpression in younger than or equal to50years of ovarian serous is not dramatically higher than that in greater than50years(P＞0.05).
Conclusion：1.The positive expression rate of OPN in ovarian serouscystadenocarcinoma tissues is much higher than those in ovarian serouscystadenoma tissues and nomal ovarian tissues(P<0.05).2.There wascorrelation between the positive expression rate of OPN with pathologicalgrading and clinical stages.3.the later clinical stage and the worsedifferentiation of ovarian serous adenocarcinoma,the stronger positiveexpression rate of OPN.4.There was no relation between OPN and the age ofthe patients.5.Overexpression of OPN may has the relationship with thedevelopment,invasion and metastasis of ovarian serous adenocarcinom. Itspotential clinical significance can be used as a prognostic marker in ovariancancer patients.
引文
[1] Senger DR, Winh DF, Hynes RO. Trausfonned mammalian ceuesecretespecific proteins and phosphoproteins[J]. Cell,1979,16(4):885-893.
[2]张果,李巍,崔恒,等.耐药性卵巢上皮性癌治疗进展[J].中华妇产科杂志,2006,41(12):343-344.
[3] Rittling SR, Chambers AF. Role of osteopontin in tumor progression[J]. BrJ Cancer,2004,90(10):1877-1881.
[4] Meshkova IE, Kostromina EV, Trouk EB. Diagnostic potentin ofultrasound examination for tumor recurrence and metastasis[J]. Vo-pronkol,2000,46(1):84-87.
[5] Lyins EL, Pavlik EL, Andrykowski MA. Validity of self reports of returnfor routine repeat screen ing in an ovarian cancer screening program[J].Cancer Epidemiol Biomarkers Prev,2007,16(3):490-493.
[6] Rehn M, Perel P, Blackhall K, et al. Prognostic models for the early care oftraumapatients: a systematic review[J]. Scand J Trauma Resuse EmergMed,2011,19:18040-18047.
[7]穆玉兰,刘鸣,汤春生.卵巢癌筛查研究进展[J].中国实用妇科与产科杂志,2007,23(10):804-805.
[8] Menon U, Skates SJ, Lewis S, et al. Prospective study using the risk ofovarian cancer algorithm to screen for ovarian cancer[J]. J Clin Oncol,2005,23(31):7919-7926.
[9]曹泽毅.妇产常见肿瘤[M].第3版.北京:人民卫生出版社,2010,84-86.
[10] Fisher LW, Torchia DA, Fohr B, et al. Flexible structures of SIBLINGProteins, Bone Sialoprotein, and Osteopontin[J]. Biochem Biophys ResCommun,2001,280(2):460-465.
[11]Hu CC, Hart TC, Dupont BR, et al. Cloning human enamelin cDNA,chromosomal localization, and analysis of expression during toothdevelopment[J]. J Dent Res,2000,79(4):912-919.
[12]Fisher LW, Fedarko NS. Six genes expressed in bones and teeth encode thecurrent members of the BIBLING family of proteins[J]. Connect TissueRes,2003,44(Suppl1):33-40.
[13]Sodek J, Ganss B, McKee MD. Osteopontin[J]. Crit Rev Oral Biol Med,2000,11(3):279-303.
[14]Jain A, Karadag A, Fohr B, et al. Three SIBLINGs (small integrin-bindingligand, N-linked glycoproteins) enhance factor H's cofactor activityenabling MCP-like cellular evasion of complement-mediated attack[J]. JBiol Chem,2002,277(16):13700-13708.
[15]Ogbureke KU, Fish LW. Expression of BIBLINGs and their partner MMpsin salivary glands[J]. J Dent Res,2004,83(9):664-670.
[16]Giachelli CM, Steitz S. Osteopontin:a versatile regulator of inflammationand biomineralization[J]. Matrix Biol,2000,19(7):615-622.
[17]Fedarko NS, Fohr B, Robey PG, et al. Factor H binding to bonesialoprotein and osteopontin enables tumor cell evasion ofcomplement-mediated attack[J]. J Biol Chem,2000,275(22):16666-16672.
[18]Gajardo H, Barrerad G. Quality control of bone densitometry: precision,reprodcility, and clinical application[J]. Rev Med Chil,1998,126(1):56-62.
[19]El-Tanani MK, Campbell FC, Kurisetty V, et a1. The regulation and role ofosteopontin in malignant transformation and cancer[J]. Cytokine GrowthFactor Rev,2006,17(6):463-474．
[20]Wai PY, Kuo PC. Osteopontin: regulation in tumor metastasis[J]. CancerMetastasis Rev,2008,27(1):103-118．
[21]Tuck AB, Chambers AF, Allan AL. Osteopontin overexpression in breastcancer: knowledge gained and possible implications for clinicalmanagement[J]. J Cell Biochem,2007,102(4):859-868．
[22]Samant RS, Clark DW, Fillmore RA, et al. Breast caneer metastasissuppressor I (BRMSI) inhibits osteopontin transcriplion by abrogatingNF-kappaB activation[J]. Mol Cancer,2007,16:6-6.
[23]Vaidya KS, Welch DR. Metastasis suppressors and their roles in breastcarcinoma[J]. J Mammary Gland Biol Neoplasia,2007,12(2-3):175-190．
[24]Lei H, Juan AH, Kim MS, et al. Identification of a Hoxc8-re-gulatedtranscriptional network in mouse embryo fibroblast cells[J]. Proc NatlAcad Sci USA,2006,103(27):10305-10309.
[25]Yousef GM, Diamandis EP. An overview of the kallikrein gene families inhumans and other species: Emerging candidate tumour markers[J]. ClinBiochem,2003,36(6):443.
[26]Higashibata Y, Sakuma T, Kawahata H, et al. Identification of promoterregions involved in cell and developmental stage-specific osteopontinexpression in bone kidney,placenta,and mammary gland:an analysis oftransgenic mice[J]. J Bone Miner Res,2004,19(1):78-88.
[27]Kon S, Maeda M, Segawa T, et al. Antibodies to different peptides inosteopontin reveal complexities in the various secreted forms[J]. J CellBiochem,2000,77(3):487-498.
[28]Christensen B, Petersen TE, Sqrensen ES, et al. Post-translationalmodification and proteolytic processing of urinary osteopontin[J]. J BiolChem,2008,411:53-61.
[29]Christensen B, Kazanecki CC, Petersen TE, et al. Cell typespecificpost-translational modification of mouse osteopontin are associated withdifferent adhesive properties[J]. J Biol Chem,2007,282(27):19463-19472.
[30] Hirama M, Takahashi F, Takahashi K, et al. Osteopentin overproduced bytumor cells acts as a potent angiogenic factor contributing to tumorgrowth[J]. Cancer Lett,2003,198(1):107-117.
[31]Brown LF, Papadopoulos SA, Berse B, et al. Osteopontin expression anddistribution in human carcinomas[J]. Am Pathol,1994,145(4):610-623.
[32]Fedarko NS, Jain A,Karadag A, et a1. Elevated serum bone sialoproteinand osteopontin in colon, breast, prostate,and lung cancer. Clin Cancer Res,2001,7(12):4060-4066.
[33]Coppola D, Szabo M, Boulware D, et a1. Correlation of osteopontinproteinexpression and pathological stage across a wide variety oftumorhistologies[J]. Clin Cancer Res,2004,10(1):184-190.
[34]Koopmann J, Fedarko NS, Jain A, et a1. Evaluation of osteoponfin asbiomarker for pancreatic adenocarcinoma[J]. Cancer EpidemiolBiomarkers Prev,2004,13(3):487-491.
[35]Wong TS, Kwong DL, Sham J, et a1. Elevation of plasma osteopontin levelin patients with undifferentiated nasophmyngeal carcinoma[J]. Eur J SurgOncol,2005,31(5):555-558.
[36]Bellahcene A, Castronovo V. Increased expression of osteonectin andosteopontin,two bone matrix proteins, in human breast cancer[J]. Am JPathol,1995,146(1):95-100.
[37]Chambers AF, Wilson SM, Kerkvliet N, et al. Osteopontin expression inlung cancer[J]. Lung Cancer1996,145(3):311-323.
[38]Subha P, Anuardha B, Gopal CK. Osteopontin stimulates tumor growth andactivation of promatrix metalloproteinase-2throouth nuclear matrixfactor-kB-mediated induction of membrane type I matrix metalloproteinasein murine membrane cells[J]. J Biol Chem,2001,276(48):44926-44935.
[39]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin over produced bytumor cells acts as a potent angiogenic factor contributing to tumorgrowth[J]. Cancer Lett,2003,198(1):107-117.
[40]Bramwell VH, Doig GS, Tuck AB, et al. Serial plasma osteopontin levelshave prognostic value in metastatic breast cancer[J]. Clin Cancer Res,2006,12(11):3337-3343.
[41]Hotte SJ, Winquist EW, Stitt L et al. Plasma osteoponti:associations withsurvival and metasis tobone in men with hormone-refractory prostatecarcinoma. Cancer,2002,95(3):506-512.
[42]Ito T, Hashimoto Y, Tanaka E, et al. An inducible short-hairpin RNA vectoragainst osteopontin reduces metastatic potential of human esophagealsquamous cell carcinoma in vitro and in vivo[J]. Clin Cancer Res,2006,12(4):1308-1316.
[43]Tuek AB, O’Malley FP, Singhal H, et al. Osteopontin and p53expressionare associated with tumor progression in a case of synchronous, bilatel,invasive mammary carcinomas. Arch Pathol Lab Med,1997,121(6):578-584.
[44]Kriunin P, Urquidi V, LUBMAN DM, et a1. Identification ofmetastasis-associated proteins in a human tumor metastasis model usingthe mass-mapping technique[J]. Proteomics,2004,4(9):2754-2765．
[45]Kim JH, Skates SJ, Uede T, et al. Osteopontin as a potential diagnosticbiomarker for ovarian cancer[J]. JAMA,2002,287(13):1671-1679.
[46]Ye B, Skates S, Mok SC, et al. Proteomie-based discovery andcharacterization of glycosylated eosinophil-derived neurotoxin andCooH-terminal osteepontin f ragments for ovarian cancer in urine[J]. ClinCancer Res,2006,12(2):432-441．
[47]Vrzalova J, Prazakova M, Novotny Z, et al. Test of ovarian cancermultiplex xMAP technology panel[J]. Anticancer Res,2009,29(2):573-576.
[48]Hwang J, Na S, Lee H, et al. Correlation between preoperative serumlevels of five biomarkers and relation ships between these biomarkers andcancer stage in epithelial overian cancer[J]. J Gynecol Oncol,2009,20(3):169-175.
[54]马哲,张虹.骨桥蛋白在卵巢组织中的表达及临床意义[J].现代诊断与治疗,2011,22(3):131-133.
[50]Brakora KA, Lee H, Yusuf R, et al. Utility of osteopontin as a biomarker inrecurrent epithelial ovarian cancer[J]. Gyneco Onco,2004,93(2):361-365．
[51]董晓瑜,杨静华,王慧兰.骨桥蛋白在卵巢上皮性癌组织和血清中的表达及其意义[J].中国结合临床,2008,24(8):760-762.
[52]谭同焕,关婷,况玉兰.等.骨桥蛋白在卵巢肿瘤组织中的表达及其临床意义[J].肿瘤防治研究,2009,36(1):47-50.
[53]范银芬,尚艳红,李筱梅.骨桥蛋白在卵巢上皮性癌中的表达及意义[J].中华实用诊断与治疗杂志,2010,24(4):409-411.
[54]张丽丽,邵淑丽,武燕. OPN和B7-H4在上皮性卵巢肿瘤中的表达及意义[J].癌症,2010,29(1):25-29.
[55]李艳艳,张松灵,张晓霞.卵巢浆液性囊腺癌组织中骨桥蛋白的表达及其临床意义[J].吉林大学学报医学报,2012,38(1):123–126.
[56]Mattem J, Koomagi R, Volm M. Association of vascular endothelial growthfactor expression with int ratumoral microvessel density and tumor cellproliferation in human epidermoid lung carcinoma[J]. Br J Cancer,1996,73(7):931-934.
[57]王影.255例妇科住院患者血清CA125分析[D].长春:吉林大学第一临床医院,2009.
[58]Maki M, Hirota S, Kaneko Y, et al. Expression of osteopont in messengerRNA by macrophages in ovarian serous papillary cystadenocarcinoma:apossible association with calcification of psammom a bodies[J]. Pathol Int,2000,50(7):531-535.
[59]Rosen DG, Wang L, Atk inson JN, et al. Potential markers that complementexpression of CA125in epithelial ovarian cancer[J]. Gynecol Oncol,2005,99(2):267-277.
[60]Nakae M, Iwamoto I, Fujino T, et al. Preoperative plasma osteopontin leveas biomarker complementary to carbohydrate antigen125in predictingovarian cancer[J]. J Obstet Gynaecol Rrs,2006,32(3):309-314.
[2]张果,李巍,崔恒,等.耐药性卵巢上皮性癌治疗进展[J].中华妇产科杂志,2006,41(12):343-344.
[3] Rittling SR, Chambers AF. Role of osteopontin in tumor progression[J]. BrJ Cancer,2004,90(10):1877-1881.
[4] Meshkova IE, Kostromina EV, Trouk EB. Diagnostic potentin ofultrasound examination for tumor recurrence and metastasis[J]. Vo-pronkol,2000,46(1):84-87.
[5] Lyins EL, Pavlik EL, Andrykowski MA. Validity of self reports of returnfor routine repeat screen ing in an ovarian cancer screening program[J].Cancer Epidemiol Biomarkers Prev,2007,16(3):490-493.
[6] Rehn M, Perel P, Blackhall K, et al. Prognostic models for the early care oftraumapatients: a systematic review[J]. Scand J Trauma Resuse EmergMed,2011,19:18040-18047.
[7]穆玉兰,刘鸣,汤春生.卵巢癌筛查研究进展[J].中国实用妇科与产科杂志,2007,23(10):804-805.
[8] Menon U, Skates SJ, Lewis S, et al. Prospective study using the risk ofovarian cancer algorithm to screen for ovarian cancer[J]. J Clin Oncol,2005,23(31):7919-7926.
[9]曹泽毅.妇产常见肿瘤[M].第3版.北京:人民卫生出版社,2010,84-86.
[10] Fisher LW, Torchia DA, Fohr B, et al. Flexible structures of SIBLINGProteins, Bone Sialoprotein, and Osteopontin[J]. Biochem Biophys ResCommun,2001,280(2):460-465.
[11]Hu CC, Hart TC, Dupont BR, et al. Cloning human enamelin cDNA,chromosomal localization, and analysis of expression during toothdevelopment[J]. J Dent Res,2000,79(4):912-919.
[12]Fisher LW, Fedarko NS. Six genes expressed in bones and teeth encode thecurrent members of the BIBLING family of proteins[J]. Connect TissueRes,2003,44(Suppl1):33-40.
[13]Sodek J, Ganss B, McKee MD. Osteopontin[J]. Crit Rev Oral Biol Med,2000,11(3):279-303.
[14]Jain A, Karadag A, Fohr B, et al. Three SIBLINGs (small integrin-bindingligand, N-linked glycoproteins) enhance factor H's cofactor activityenabling MCP-like cellular evasion of complement-mediated attack[J]. JBiol Chem,2002,277(16):13700-13708.
[15]Ogbureke KU, Fish LW. Expression of BIBLINGs and their partner MMpsin salivary glands[J]. J Dent Res,2004,83(9):664-670.
[16]Giachelli CM, Steitz S. Osteopontin:a versatile regulator of inflammationand biomineralization[J]. Matrix Biol,2000,19(7):615-622.
[17]Fedarko NS, Fohr B, Robey PG, et al. Factor H binding to bonesialoprotein and osteopontin enables tumor cell evasion ofcomplement-mediated attack[J]. J Biol Chem,2000,275(22):16666-16672.
[18]Gajardo H, Barrerad G. Quality control of bone densitometry: precision,reprodcility, and clinical application[J]. Rev Med Chil,1998,126(1):56-62.
[19]El-Tanani MK, Campbell FC, Kurisetty V, et a1. The regulation and role ofosteopontin in malignant transformation and cancer[J]. Cytokine GrowthFactor Rev,2006,17(6):463-474．
[20]Wai PY, Kuo PC. Osteopontin: regulation in tumor metastasis[J]. CancerMetastasis Rev,2008,27(1):103-118．
[21]Tuck AB, Chambers AF, Allan AL. Osteopontin overexpression in breastcancer: knowledge gained and possible implications for clinicalmanagement[J]. J Cell Biochem,2007,102(4):859-868．
[22]Samant RS, Clark DW, Fillmore RA, et al. Breast caneer metastasissuppressor I (BRMSI) inhibits osteopontin transcriplion by abrogatingNF-kappaB activation[J]. Mol Cancer,2007,16:6-6.
[23]Vaidya KS, Welch DR. Metastasis suppressors and their roles in breastcarcinoma[J]. J Mammary Gland Biol Neoplasia,2007,12(2-3):175-190．
[24]Lei H, Juan AH, Kim MS, et al. Identification of a Hoxc8-re-gulatedtranscriptional network in mouse embryo fibroblast cells[J]. Proc NatlAcad Sci USA,2006,103(27):10305-10309.
[25]Yousef GM, Diamandis EP. An overview of the kallikrein gene families inhumans and other species: Emerging candidate tumour markers[J]. ClinBiochem,2003,36(6):443.
[26]Higashibata Y, Sakuma T, Kawahata H, et al. Identification of promoterregions involved in cell and developmental stage-specific osteopontinexpression in bone kidney,placenta,and mammary gland:an analysis oftransgenic mice[J]. J Bone Miner Res,2004,19(1):78-88.
[27]Kon S, Maeda M, Segawa T, et al. Antibodies to different peptides inosteopontin reveal complexities in the various secreted forms[J]. J CellBiochem,2000,77(3):487-498.
[28]Christensen B, Petersen TE, Sqrensen ES, et al. Post-translationalmodification and proteolytic processing of urinary osteopontin[J]. J BiolChem,2008,411:53-61.
[29]Christensen B, Kazanecki CC, Petersen TE, et al. Cell typespecificpost-translational modification of mouse osteopontin are associated withdifferent adhesive properties[J]. J Biol Chem,2007,282(27):19463-19472.
[30] Hirama M, Takahashi F, Takahashi K, et al. Osteopentin overproduced bytumor cells acts as a potent angiogenic factor contributing to tumorgrowth[J]. Cancer Lett,2003,198(1):107-117.
[31]Brown LF, Papadopoulos SA, Berse B, et al. Osteopontin expression anddistribution in human carcinomas[J]. Am Pathol,1994,145(4):610-623.
[32]Fedarko NS, Jain A,Karadag A, et a1. Elevated serum bone sialoproteinand osteopontin in colon, breast, prostate,and lung cancer. Clin Cancer Res,2001,7(12):4060-4066.
[33]Coppola D, Szabo M, Boulware D, et a1. Correlation of osteopontinproteinexpression and pathological stage across a wide variety oftumorhistologies[J]. Clin Cancer Res,2004,10(1):184-190.
[34]Koopmann J, Fedarko NS, Jain A, et a1. Evaluation of osteoponfin asbiomarker for pancreatic adenocarcinoma[J]. Cancer EpidemiolBiomarkers Prev,2004,13(3):487-491.
[35]Wong TS, Kwong DL, Sham J, et a1. Elevation of plasma osteopontin levelin patients with undifferentiated nasophmyngeal carcinoma[J]. Eur J SurgOncol,2005,31(5):555-558.
[36]Bellahcene A, Castronovo V. Increased expression of osteonectin andosteopontin,two bone matrix proteins, in human breast cancer[J]. Am JPathol,1995,146(1):95-100.
[37]Chambers AF, Wilson SM, Kerkvliet N, et al. Osteopontin expression inlung cancer[J]. Lung Cancer1996,145(3):311-323.
[38]Subha P, Anuardha B, Gopal CK. Osteopontin stimulates tumor growth andactivation of promatrix metalloproteinase-2throouth nuclear matrixfactor-kB-mediated induction of membrane type I matrix metalloproteinasein murine membrane cells[J]. J Biol Chem,2001,276(48):44926-44935.
[39]Hirama M, Takahashi F, Takahashi K, et al. Osteopontin over produced bytumor cells acts as a potent angiogenic factor contributing to tumorgrowth[J]. Cancer Lett,2003,198(1):107-117.
[40]Bramwell VH, Doig GS, Tuck AB, et al. Serial plasma osteopontin levelshave prognostic value in metastatic breast cancer[J]. Clin Cancer Res,2006,12(11):3337-3343.
[41]Hotte SJ, Winquist EW, Stitt L et al. Plasma osteoponti:associations withsurvival and metasis tobone in men with hormone-refractory prostatecarcinoma. Cancer,2002,95(3):506-512.
[42]Ito T, Hashimoto Y, Tanaka E, et al. An inducible short-hairpin RNA vectoragainst osteopontin reduces metastatic potential of human esophagealsquamous cell carcinoma in vitro and in vivo[J]. Clin Cancer Res,2006,12(4):1308-1316.
[43]Tuek AB, O’Malley FP, Singhal H, et al. Osteopontin and p53expressionare associated with tumor progression in a case of synchronous, bilatel,invasive mammary carcinomas. Arch Pathol Lab Med,1997,121(6):578-584.
[44]Kriunin P, Urquidi V, LUBMAN DM, et a1. Identification ofmetastasis-associated proteins in a human tumor metastasis model usingthe mass-mapping technique[J]. Proteomics,2004,4(9):2754-2765．
[45]Kim JH, Skates SJ, Uede T, et al. Osteopontin as a potential diagnosticbiomarker for ovarian cancer[J]. JAMA,2002,287(13):1671-1679.
[46]Ye B, Skates S, Mok SC, et al. Proteomie-based discovery andcharacterization of glycosylated eosinophil-derived neurotoxin andCooH-terminal osteepontin f ragments for ovarian cancer in urine[J]. ClinCancer Res,2006,12(2):432-441．
[47]Vrzalova J, Prazakova M, Novotny Z, et al. Test of ovarian cancermultiplex xMAP technology panel[J]. Anticancer Res,2009,29(2):573-576.
[48]Hwang J, Na S, Lee H, et al. Correlation between preoperative serumlevels of five biomarkers and relation ships between these biomarkers andcancer stage in epithelial overian cancer[J]. J Gynecol Oncol,2009,20(3):169-175.
[54]马哲,张虹.骨桥蛋白在卵巢组织中的表达及临床意义[J].现代诊断与治疗,2011,22(3):131-133.
[50]Brakora KA, Lee H, Yusuf R, et al. Utility of osteopontin as a biomarker inrecurrent epithelial ovarian cancer[J]. Gyneco Onco,2004,93(2):361-365．
[51]董晓瑜,杨静华,王慧兰.骨桥蛋白在卵巢上皮性癌组织和血清中的表达及其意义[J].中国结合临床,2008,24(8):760-762.
[52]谭同焕,关婷,况玉兰.等.骨桥蛋白在卵巢肿瘤组织中的表达及其临床意义[J].肿瘤防治研究,2009,36(1):47-50.
[53]范银芬,尚艳红,李筱梅.骨桥蛋白在卵巢上皮性癌中的表达及意义[J].中华实用诊断与治疗杂志,2010,24(4):409-411.
[54]张丽丽,邵淑丽,武燕. OPN和B7-H4在上皮性卵巢肿瘤中的表达及意义[J].癌症,2010,29(1):25-29.
[55]李艳艳,张松灵,张晓霞.卵巢浆液性囊腺癌组织中骨桥蛋白的表达及其临床意义[J].吉林大学学报医学报,2012,38(1):123–126.
[56]Mattem J, Koomagi R, Volm M. Association of vascular endothelial growthfactor expression with int ratumoral microvessel density and tumor cellproliferation in human epidermoid lung carcinoma[J]. Br J Cancer,1996,73(7):931-934.
[57]王影.255例妇科住院患者血清CA125分析[D].长春:吉林大学第一临床医院,2009.
[58]Maki M, Hirota S, Kaneko Y, et al. Expression of osteopont in messengerRNA by macrophages in ovarian serous papillary cystadenocarcinoma:apossible association with calcification of psammom a bodies[J]. Pathol Int,2000,50(7):531-535.
[59]Rosen DG, Wang L, Atk inson JN, et al. Potential markers that complementexpression of CA125in epithelial ovarian cancer[J]. Gynecol Oncol,2005,99(2):267-277.
[60]Nakae M, Iwamoto I, Fujino T, et al. Preoperative plasma osteopontin leveas biomarker complementary to carbohydrate antigen125in predictingovarian cancer[J]. J Obstet Gynaecol Rrs,2006,32(3):309-314.