乳腺癌中shh,ptch和smo蛋白过表达的临床病理学意义
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摘要
目的:研究Hedgehog信号通路中shh,ptch和smo蛋白过表达在乳腺浸润性导管癌及导管内原位癌中的临床病理学意义。
     方法:采用免疫组化EnVision方法检测111例浸润性导管癌、40例导管内原位癌和21例正常乳腺导管上皮组织芯片中shh,ptch和smo蛋白的表达情况,并分析其相关性。
     结果:shh、ptch和smo蛋白在正常导管上皮中表达阴性或弱阳性,但在浸润性导管癌(shh:74.8%,ptch:68.5%,smo:65.8%)和导管内原位癌(shh:100%,ptch:100%,smo:90%)中阳性表达率明显增高,差异有统计学意义(均P<0.001)。乳腺导管癌中shh蛋白的表达率在Ki67和c-erbB2阳性组明显高于阴性组(均P<0.05);而且与淋巴结转移相关(P<0.05)。此外,shh、ptch和smo蛋白表达与乳腺癌患者的年龄、ER、PR、p53蛋白的表达及组织学分级和临床分期等特征均无显著性关系。Spearman相关分析显示,在乳腺癌组织中shh的表达分别与ptch(r=0.55,P<0.01)、smo(r=0.58,P<0.01)的表达呈正相关;而且ptch的表达又与smo的表达呈正相关(r=0.495,P<0.01)。
     结论:shh、ptch和smo蛋白表达检测可以作为乳腺癌的早期辅助诊断指标,而且shh对判定乳腺癌的预后有一定的作用。
Objective:To investigate the clinicopathological significance of shh, ptch and smo protein overexpression in breast invasive ductal carcinoma and ductal carcinoma in situ (DCIS).
     Methods:The expression of shh, ptch and smo proteins was detected by EnVision method of immunohistochemistry in tissue-microarray making from 111 cases of breast invasive ductal carcinoma,40 cases of DCIS,and 21 cases of normal breast ductal epithelium tissues, and their correlations were analyzed.
     Results:The immunohistochemical staining showed that the expressions of shh,ptch and smo in normal ductal epithelium were completely absent or rare, but significantly higher in invasive ductal carcinoma (shh:74.8%, ptch:68.5%,smo:65.8%) and DCIS (shh:100%, ptch:100%, smo:90%) than in normal ductal epithelium (all P<0.001).In ductal carcinoma, shh protein expression rate was significantly higher in both of Ki67 and c-erbB2 positive groups than negative groups (all P<0.05), and was correlated to lymph node metastasis (P<0.05).Whereas the expression of shh, ptch and smo in breast cancer showed no correlation to patients'age, ER, PR, p53 protein expression, tissue grade, and clinical stage. Spearman correlation analysis showed that shh expression was positively correlated to ptch (r=0.55,P<0.01)and smo (r=0.58,P<0.01)expression,respectively; and ptch expression was positively correlated to smo expression (r=0.495,P<0.01).
     Conclusion:shh,ptch and smo protein overexpression might be a helpful marker for the early diagnosis of breast cancer, and the detection of shh might be helpful for indicating the prognosis of the breast cancer.
引文
[1]Katoh Y,Katoh M.Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA[J].Int J Mol Med,2008,22(3):271-275.
    [2]Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis[J].Nature.2004;432(7015):324-31.
    [3]Ruizi Altaba A, Mas C,Stecca B.The Gli code:an information nexus regulating cell fate,sternness and cancer[J].Trends Cell Biol.2007;17(9):438-47.
    [4]Wetmore C.Sonic hedgehog in normal and neoplastic proliferation:insight gained from human tumors and animal models[J].Curr Opin Genet Dev.2003;13(1):34-42.
    [5]Cohen MM Jr.The hedgehog signaling network [J].Am J Med Genet A.2003;123(1): 5-28.
    [6]Ruizi Altaba A.Gli proteins and hedgehog signaling:development and cancer[J]. Trends Genet.1999(10);15:418-25.
    [7]Matise MP, Joyner AL.Gli genes in development and cancer[J].Oncogene.1999; 18(55):7852-59.
    [8]Wechsler-Reya R, Scott MP.The developmental biology of brain tumors[J].Annu Rev Neurosci.2001;24:385-428.
    [9]Watkins DN,Berman DM, Burkholder SG,et al.Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer[J].Nature.2003;422(6929):313-17.
    [10]Kubo M, Nakamura M, Tasaki A, et al.Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer[J].Cancer Res.2004;64(17):6071-74.
    [11]Oniscu A,James RM, Morris RG,et al.Expression of Sonic hedgehog pathway genes is altered in colonic neoplasia[J].J Pathol.2004;203(4):909-17.
    [12]Kubo M,Nakamura M,Tasaki A,et al.Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer [J].Cancer Res, 2004,64(17):6071-6074.
    [13]Greene F L, Page D L, Fleming I D, et al.American Joint Committee on Cancer Staging Manual [M].6th ed,Chicago,USA:Springer,2002:139-144.
    [14]周隽,王军臣,卢婉平,等.PTEN与预后相关因子在乳腺癌组织芯片中的相关性[J]. 肿瘤,2007,27(9):723-726.
    [15]Xuan YH, Lin Z.Expression of Indian Hedgehog signaling molecules in breast cancer [J].J Cancer Res Clin,2009,135(2):235-240.
    [16]Liu S,Dontu G, Mantle ID,et al.Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cell [J].Cancer Res, 2006,66:6063-6071.
    [17]Clement V, Sanchez P,de TN,et al.HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal,and tumorigenicity [J].Curr Biol, 2007,17:165-172.
    [1]Cohen MM Jr. The hedgehog signaling network. Am J Med Genet A.2003;123(1): 5-28.
    [2]Wilbanks AM, Fralish GB,Kirby ML, et al.P-Arrestin 2 regulates zebrafish development through the Hedgehog signaling pathway. Science,2004;306 (5705): 2264-7.
    [3]Porter JA, Young KE, Beachy PA.Cholesterol modification of hedgehog signaling proteins in animal development. Science.1996;274(5285):255-259.
    [4]Porter JA, Ekker SC,Park WJ, et al.Hedgehog patterning activity:role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell,1996;86(1):21-34.
    [5]Ma Y, Erkner A, Gong R, et al.Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell,2002;111(1):63-75.
    [6]Chen Y, Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. Cell,1996;87(3):553-563.
    [7]Alcedo J, Ayzenzon M, Ohlen TV, et al.The Drosophila smoothened gene encodes seven-pass membrane protein, a putative receptor for hedgehog signal.Cell,1996; 86(2):221-232.
    [8]Nybakken K, Perrimon N.Hedgehog signal transduction:recent findings.Curt Opin Genet Dev,2002;12(5):503-511.
    [9]Xin Z, Goetz J A, Suber L M, et al.A freely diffusible form of Sonic hedgehog mediates long-range signaling. Nature,2001;411 (6838):716-720.
    [10]Wicking C,Smyth I, Bale A. The hedgehog signalling pathway in tumorigenesis and development. Oncogene,1999;18(55):7844-7851.
    [11]Sekimizu K, Nishioka N,Sasaki S,et al.The zebrafish iguanalocus encodes Dzipl, a novel zinc-finger protein required for proper regulation of Hedgehog signaling. Development,2003;131(11):2521-2532.
    [12]Taipale J,Beachy PA.The Hedgehog and Wnt signaling pathways in cancer. Nature, 2001;411(6835):349-354.
    [13]Chuang P T, Mcmahon A P.Vertebrate Hedgehog signaling modulated by induction of a Hedgehog-binding protein. Nature,1999; 397(6720):617-621.
    [14]Petrosky N S,Tassava R A, Olsen C L, et al.Hedgehog interacting protein is highly expressed in endothelial cells but downregulated during angiogenesis and in several human tumors. BMC Cancer,2004;4(1):43.
    [15]Jia J, Tong C,Jiang J.Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail.Genes Dev,2003; 17(21):2709-2720.
    [16]Kenney A M, Cole M D, Rowitch D H. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development,2003;130(1):15-28.
    [17]Rahnama F, Toftgard R, Zaphiropoulos PG. Distinct roles of PTCH2 splice variants in Hedgehog signaling. Biochem.2004; 378(2):325-334.
    [18]Daya-Grosjean L, Sarasin A. UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients. Mutat.Res.2000;450(1-2):193-199.
    [19]Tojo M, Kiyosawa H, Iwatsuki K, et al.Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma. Br. J. Dermatol.2003;148(5):892-897.
    [20]Regl G, Neill GW, Eichberger T, et al.Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene 2002;21(36):5529-5539.
    [21]Regl G, Kasper M, Schnidar H, et al.The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene 2004; 23(6):1263-1274.
    [22]Ikram MS, Neill GW, Regl G, et al.GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter.J.Invest. Dermatol. 2004;122(6):1503-1509.
    [23]Oro AE, Higgins K. Hair cycle regulation of Hedgehog signal reception.Dev. Biol. 2003;255(2):238-248.
    [24]Podlasek CA, Barnett DH,Clemens JQ,et al.Prostate Development Requires Sonic Hedgehog Expressed by the Urogenital Sinus Epithelium. Developmental Biology. 1999;209(1):28-29.
    [25]Karhadkar SS,Isaacs JT, Beachy PA, et al.Hedgehog signalling in prostate regeneration neoplasia and metastasis.Nature,2004;435:707-712.
    [26]Sanchez P, Hernandez A M, Stecca B,et al.Inhibition of prostate cancer proliferation by interference with sonic hedgehog-glil signaling. Proc Natl Acad Sci, 2004;101(34):12561-12566.
    [27]Van Tuyl M, Post M. From fruitflies to mammals:mechanisms of signalling via the sonic hedgehog pathway in lung development. Respir Res.2000;1(1):30-35.
    [28]Watkins D N, Berman D M, Burkholder S G, et al.Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature,2003;422 (6929): 313-317.
    [29]Nishimaki H, Kasai K, Kozaki K, et al.A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun,2004;314(2):313-320.
    [30]Hebrok M. Hedgehog signaling in pancreas development. Mech. Dev.2003;120 (1): 45-57.
    [31]Berman DM, Karhadkar SS,Maitra A, et al.Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.Nature 2003;425 (6960): 846-851.
    [32]Thayer SP, Magliano MP, Heiser PW, et al.Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425(6960):851-856.
    [33]Dimmler A, Brabletz T, Hlubek F, et al.Transcription of sonic hedgehog, a potential factor for gastric morphogenesis and gastric mucosa maintenance, is up-regulated in acidic conditions.Lab Invest,2003;83(12):1829-1837.
    [34]Ma X, Chen K, Huang S,et al.Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas.Carcinogenesis,2005;26(10):1698-1705.
    [35]Xie J,Johnson RL,Zhang X,et al.Mutations of PATCHED gene in several types of sporadic extracutaneous tumor.CancerRes,1997;57(2):2369-2372.
    [36]Vorechovsky 1,Benediktsson KP, Toftgard R. The patched/hedgehog/smoothened signaling pathway in human breast cancer:No evidence for H133Y SHH, PTCH, and SMO mutations. Eur J Cancer,1999;35(5):711-713.
    [37]Kubo M, Nakamura M, Tasaki A et al.Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. CancerRes, 2004;64(17):6071-6074.
    [38]Chang Claude J, Dunning A, Schnitzbauer U, et al.The patched polym orphism Prol315Leu (C3944T)may modulate the association between use of oral contraceptives and breast cancer risk. Int J Cancer,2003;103(6):779-783.
    [39]Lobjois V, Benazeraf B,Bertrand N, et al.Specific regulation of cyclins D1 and D2 by FGF and Shh signaling coordinates cell cycle progression,patterning and differentiation during early steps of spinal cord development. Dev Biol, 2004;273(2):195-209.
    [40]Terry MB,Gammon MD, Schoenberg JB,et al.Oral Contraceptive Use and Cyclin Dl OverexpressiOn in Breast Cancer among Young Women. Cancer Epidemiol Biomar Prevent,2002;11(10pt1):1100-1103.
    [41]Molly D S, Li W, Xin S J. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.Nature,2002;417(6886):299-304.