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巨噬细胞移动抑制因子在前列腺癌患者血清中的表达及其与PSA的关系
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摘要
目的探讨前列腺癌患者血清巨噬细胞移动抑制因子(macrophage migration inhibitory factor, MIF)水平与其临床特征和前列腺特异抗原(PSA)的关系。方法用酶联免疫吸附法(ELISA)检测原发性前列腺癌、良性前列腺增生(BPH)、健康成年男性的血清MIF水平,同时用时间分辨荧光免疫分析法(TRFIA)检测各组血清PSA水平。结果前列腺癌组血清中的MIF表达率为100%(40/40),BPH组为70%(14/20),正常对照组为85%(17/20)。前列腺癌组血清中MIF的浓度与BPH组及正常对照组有显著差异(P<0.0001) ,而BPH组与正常对照组相比无明显差异(P>0.05)。MIF表达与前列腺癌分化程度、分期呈显著相关(P<0.05),但与骨转移无明显相关(P >0.05)。前列腺癌组的PSA与BPH组、正常对照组有显著差异(P<0.0001) ,而BPH组与正常对照组相比也有显著差异( P <0.0001)。但PSA与前列腺癌分化程度、分期、骨转移无明显相关(P >0.05)。血清中MIF浓度和PSA浓度不相关(r2=0.111, P >0.05)。结论前列腺癌患者血清中MIF高表达,且与肿瘤分化、分期显著相关,与骨转移不相关。提示MIF在前列腺癌细胞癌变、侵袭、转移过程中起着复杂、重要的作用,可能作为前列腺癌早期诊断、治疗和预后的一个生物标记物之一;但不能提高PSA诊断前列腺癌的敏感性和特异性。
Objective To observe the expression of macrophage migration inhibition factor(MIF) in serum of patients with prostate cancer and its correlation with prostate specific antigen(PSA).Methods The levels of serum MIF were measured by an enzyme linked immunosorbent assay(ELISA)in patients with prostate cancer ,patients with benign prostatic hyperplasia(BPH) and healthy male adults as healthy controls.The serum PSA level was measured using a time resolved fluoroisnmunoassay (TRFIA). Results The positive rates of MIF in serum of prostate cancer、BPH and healthy controls were 100%(40/40)、70%(14/20)and 85%(17/20)respectively.The MIF levels of patients with prostate cancer were significantly higher than those of the other two groups (P<0.0001), But there was no difference in serum levels between BPH and healthy controls (P>0.05). MIF expression was found to relate to the clinical stages and the degree of cell differentiation of prostate cancer (P<0.05), but not to bone metastasis (P>0.05). PSA was expressed more obviously in prostate cancer than in other two groups (P<0.0001), and The PSA levels of BPH were significantly higher than those of the healthy controls, But PSA expression was found to be not related to the clinical stages、the degree of cell differentiation and bone metastasis of prostate cancer (P>0.05).The MIF levels was not correlated with PSA in all serums (r2=0.111, P >0.05). Conclusions The levels of MIF were correlated significant -ly with the stage and grade of prostate cancer. MIF may play an important role in the oncogenesis and development of prostate cancer. It may be used as an candidate indicator for diagnosis、therapy and prognosis of prostate cancer. But it can not improve the sensitivity and specificity of PSA in detecting prostate cancer.
引文
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    1.Thompson IM, Pauler DK, Tangen CM, et al. The predictive value of prostate specific antigen less than 4.0 ng/ml for the diagnosis of prostate cancer. N Engl J Med. 2004;350:2239–2246.
    2.Weiser WY。Temple PA,Witek G。et aL Mdecular cloning of a Cdna encoding a human macmphagemigration inhibitory factor.PNAS,1989,86:7522—7526.
    3.Sun HW,Bernhaagen J,Bucala R,et a1.Crystal structure at 2.6 A resohtion of human macmphugemigrationinhibitory factor.PNAS.1996,93:5191—5196
    4.Fabrizio De Benedetti , Cristina M, et al. Functional and prognostic relevance of the - 173 polymorphism of the Macrophage migration inhibitory factor gene in systemic onset juvenile idiopathic arthritis [J ] . Arthritis Rheum , 2003 , 48(5) : 1398 - 1407.
    5.单志新,符永恒,余细勇,等. 巨噬细胞移动抑制因子 -173G/ C 多态性与冠心病的相关性研究(J). 中华医学遗传学杂志,2006,23(5): 548-550.
    6.周韶璋,胡品津,曾志荣.MIF-173 位点单核苷酸多态性与我国胃癌关系的研究. 中国病理生理杂志 2005 ,21(6) :1132–1135.
    7.Fingerle-Rowson G, Koch P, BikoffR, eta.l Regulation of macrophage migration inhibitory factorexpression by glucocorticoids in vivo.Am J Patho,l 2003, 162: 47-56.
    8.Bernhagen J , Calandra T , Bucala T , et al1 Regulation of the immune response by macrophage migration inhibitory factor : biological and structure features1 J Mol Med , 1998 , 76 :151-161.
    9. Bucala R1 MIF , a previously unrecognized pituitary hormone and macrophage cytokine , is a pivotal mediator in endotoxic shock1. Circulation Shock , 1994 , 44 :35-39.
    10. Rogger T,David J,Glauser MP.MIF regulates innate immune responses through modulation of Toll-like recptor 4.Nature,2001,414:920-924.
    11. Ren Y,Law S,HuangX,eta1.Maerophage migration inhibitory factor stimulates angiogenic factor expressionand correlates With diferentiation and lymph node status in patients with esophageal squamous cell carcinoma. Ann Surg,2005,242:55—63.
    12. 林曲, 黄明声, 温景芸 巨噬细胞移动抑制因子在原发性肝癌中的临床意义中山大学学报(医学科学版)2007,28(2):201-204。
    13.田慧军 王笛乐 巨噬细胞移动抑制因子在大肠癌中的表达及其与细胞凋亡的关系胃肠病学和肝病学杂志2006,15(2):206-208
    14. Bando H, Matsumoto G, Bando M Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res. 2002 Apr;93(4):389-96.
    15. Taylor JA 3rd, Kuchel GA, Hegde P Null mutation for macrophage migration inhibitory factor (MIF) is associated with less aggressive bladder cancer in mice. BMC Cancer. 2007 Jul 24;7:135.
    16. Repp AC, Mayhew ES, Apte S. Human uveal melanoma cells produce to prevent lysis by NK cells. J immunol ,2000 .165: 710-715.
    17. HUDSON J D, SHOAIBI M A, MAESTRO R, et al. A proinflammatory cytokine inhibitsp53 tumor suppressor activity[J]. J Exp Med, 1999, 190(10): 1375- 1382.
    18. Mitchell RA .I iao H,Chesney J.et a1.M acrophage migration inhibitory factor(M IF) sustains macrophage proinflam matory function by inhibiting p53: regulatory role in the innate im m une response. Proc Nat1 Acad Sci U SA .2002,99(1):345—350.
    19 Leng I .M etz CN ,Fang Y ,et a1. M IF signal transduction initiated by binding to CD74.J Exp Med,2003.197(11):1467—1476.
    20 Ren Y, Tsui HT, Poon RT Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer. 2003 Oct 20;107(1):22-9.
    21 Takahashi N,Nishihira J,Sato Y,et a1.Involvement of macmphage migration inhibitory factor (MIF)in the mechanism of tumor cell growth.Mol Mnd,l998。4:707-714.
    22 Nishihira J, Ishibashi T, Fukushima T Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor-associated angiogenesis. Ann N Y Acad Sci. 2003 May;995:171-82.
    23.Meyer-SieglerK, Fattor RA, Hudson PB. Expression of macrophage migration inhibitory factor in the human prostate. Diagn MolPatho,l 1998, 7: 44-50.
    24.Meyer-Siegler KL, Vera PL, Iczkowski KA, Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence. Genes Immun. 2007 Dec;8(8):646-52.
    25 Katherine L, Meyer-Siegler DF,Michael A. Macrophage migration inhibitory factor Evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinarma.Cancer,2002,94:1449-1456.
    26 MuramakiM, MiyakeH, YamadaY, eta.l Clinicalutility of serum Macrophage migration inhibitory factor inmenwith prostate cancer as a novel biomarker of detectionand disease progression. OncolRep.2006, 15(1): 253-257.
    27 Meyer-SieglerKL, IczkowskiKA, Vera PL. Further evidence for Increased macrophage migration inhibitory factor expression in prostate cancer. BMC Cancer, 2005, 5(1): 73.
    28 MichaelA, Stephan C, Kristiansen G, et a.l Diagnostic validity of Macrophage migration inhibitory factor in serum of patients with prostate cancer: a reevaluation. Prostate, 2005, 62(1): 34-39.
    29.Yu DS, Hsieh DS, Chang SY.Increasing expression of GST-pi MIF, and ID1 genes in chemoresistant prostate cancer cells. Arch Androl. 2006 Jul-Aug;52(4):275-81.
    30.TLin JC, Chang SY, Hsieh DS, he association of Id-1, MIF and GSTpi with acquired drug resistance in hormone independent prostate cancer cells. Oncol Rep. 2005 May;13(5):983-8.
    31.Meyer-Siegler KL, Iczkowski KA, Leng L Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol. 2006 Dec 15;177(12):8730-9.

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