STAT3和PIAS3在涎腺肿瘤中的表达及意义
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摘要
目的:
     信号传导和转录激活因子(signal transducer and activators of transcription,STAT)是一种能够介导多种细胞因子和生长因子信号向细胞核内转录的因子,其能影响靶基因的转录,也可调节细胞的功能。STAT3是STAT蛋白家族中重要成员之一,在人类许多种实体肿瘤中表现为高水平的激活状态,与肿瘤细胞的抗凋亡,增殖和血管生成关系密切,已被确定为癌基因。活化的信号转导子和转录激活子3的蛋白抑制剂(Protein inhibitor of activated signal transducer and activator of transcription 3,PIAS3)为STAT3的特异性蛋白抑制剂,其通过与活化的STAT3结合进而阻止后者与DNA结合,因而抑制STAT3的转录激活活性。有研究显示,PIAS3在人体的前列腺、脑、乳腺、肾、肺、食道、皮肤、肝脏、胃及结直肠的恶性肿瘤中都有不同程度的高表达,提示PIAS3可能在肿瘤的发生、发展的过程中起到作用。涎腺肿瘤为口腔颌面部常见的肿瘤之一,STAT3和PIAS3在涎腺肿瘤中的表达情况国内外还少见报道,因此本课题通过免疫组织化学二步法研究STAT3和PIAS3在涎腺肿瘤中的表达情况以及与STAT3和PIAS3与涎腺肿瘤恶性程度的关系。
     方法:
     采用免疫组织化学二步法检测60例涎腺肿瘤(良性涎腺肿瘤30例:包括15例多形性腺瘤,15例基底细胞腺瘤;恶性涎腺肿瘤30例:包括15例黏液表皮样癌,15例腺样囊性癌)及30例正常涎腺组织中STAT3和PIAS3的表达情况;利用自动图像分析仪定量分析STAT3和PIAS3的相对含量(灰度)。
     结果:
     1.STAT3在涎腺肿瘤及正常涎腺中的表达:STAT3在恶性肿瘤组的表达水平显著高于良性肿瘤组,两组之间有显著性差异(p<0.05);STAT3在涎腺良性肿瘤组的表达情况高于正常涎腺组,两组的表达水平亦有显著性差异(p<0.05)。
     2.PIAS3在涎腺肿瘤及正常涎腺中的表达:PIAS3在涎腺恶性肿瘤组的表达水平明显高于良性肿瘤组,两组之间的差异显著(p<0.05);涎腺良性肿瘤组中PIAS3的表达高于正常涎腺组,两组表达水平亦有显著性差异(p<0.05)。
     3.STAT3及PIAS3表达的相关性:STAT3及PIAS3在正常涎腺组织、涎腺良性肿瘤组及涎腺恶性肿瘤组中的表达呈正相关(P<0.05)。
     结论:
     STAT3及其抑制因子PIAS3在涎腺肿瘤中的表达随着涎腺肿瘤恶性程度的提高而增强,提示了STAT3及PIAS3可能影响着涎腺肿瘤的发生、发展,并且与涎腺肿瘤的恶性程度密切相关,可能成为一条治疗涎腺肿瘤的新途径。
Objective:
     STAT(signal of transducer and activators transcription) is a factor which can mediate the signal of cell factors and growth factors into nuclear. It can not only affect the transcription of target genes, but also regulate the function of cell. One of the important members of STAT is STAT3, which showed a high level of activation status in many types of human tumors.
     PIAS3 (Protein inhibitor of activated signal transducer and activator of transcription 3) is an inhibitory factor of STAT3, which can stop the combination of pSTAT3 and DNA. The researches showed that PIAS3 widely distributed in human malignant tumors.
     Salivary gland tumor is a kind of universal oral tumor, but the expressions of STAT3 and PIAS3 are rarely reported. This research is to study the expression of STAT3 and PIAS3 in salivary gland tumor.
     Methods:
     The expression of STAT3 and PIAS3 in salivary gland tumor and normal salivary gland tissues were detected by immunohistochemical assay,the automatic image analyzer was used to analyze the gray scale of the STAT3 and PIAS3.
     Results:
     (1)The positive rate of expression of STAT3 was significantly higher (p<0.05) in the group of malignant salivary gland tumor than in the group of benign salivary gland tumor,while the group of benign salivary gland was significantly higher (p<0.05) than that in normal salivary tissue.
     (2)The positive rate of expression of PIAS3 was significantly higher (p<0.05) in the group of malignant salivary gland tumor than in the group of benign salivary gland tumor,while the group of benign salivary gland was significantly higher (p<0.05) than that in normal salivary tissue.
     (3)The expression of STAT3 was positively correlated with the expression of PIAS3 in the salivary gland tumor (p<0.05) .
     Conclusion:
     The expressions of STAT3 and PIAS3 are closely related to the degree of malignance in salivary gland tumor. STAT3 and PIAS3 play an important role in the pathogenesis and development of salivary gland tumor, from which we could find a new way to treat salivary gland tumor in the further work.
引文
[1]武忠弼,杨光华.中华外科病理学(上卷)〔M〕.北京:人民卫生出版社.2006;521一539.
    [2] Lassmann S, Schuster I, Walch A, et al. STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation. J Clin Pathol. 2007; 60 (2):173~179.
    [3] Yakata Y, Nakayama T, Yoshizaki A, et al. Expression of p-STAT3 in human gastric carcinoma: significant correlation in tumour invasion and prognosis. Int J Oncol. 2007; 30 (2):437~442.
    [4] Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett. 2007; 251(2):199~210.
    [5] Jacqueline B,JamesED. The role of STATs in transcription control and Their impact on cellular function[【J】.Oncogene,2000,19:2468一2477.
    [6] Gurt MH.STAT Proteins and transcriptional responses to extracellular signals[J].Trends Biochem Sci,2000,25:496一502
    [7]何开玲.基因调控与肿瘤的发生.朱世能,主编.肿瘤基础理论.上海:上海科学技术出版社,1986,89一95.
    [8] Nakajima K, Yamanaka Y, Nakae K, et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J, 1996, 15: 3651~3658
    [9] Fernades A, Hamburger AW, Gerwin BI, et al. ErbB-2 kinaseis required for constitutive STAT3 activation in malignant human lung epithelial cells [J], IntJ Cancer, 2004, 83: 564~570
    [10]Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene Cell, 1999, 98: 295~303
    [11]Bowman T,Garcia R,Turkson J,et al. STAT in oncogenesis [J] .Oncogene,2000, 19(21): 2474~2488
    [12]Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy, Anticancer Drugs,2005, 16(6): 601~607
    [13]Bromberg JF, Wrzeszczynska MH , Devgan G , et al. Stat3 as an oncogene[J]. Ce11, 2003, 98(3): 295~303
    [14]Chung CD, Liao JY, Liu B, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science, 1997, 278 (5): 1803~1805.
    [15]Liu B, Liao J, Rao X, et al. Inhibition of Stat1-mediated gene activation by PIAS1.Proc Natl Acad Sci USA, 1998, 95 (18): 10626~10631.
    [16]Kelly A Wong, Rachel Kim, Heather Christofk, et al. Protein Inhibitor of Activated STAT Y (PIASy) and a Splice Variant Lacking Exon 6 Enhance Sumoylation but Are Not Essential for Embryogenesis and Adult Life. Molecular and Cellular Biology, 2004; 24 (12): 5577~5586。
    [17]Ueki N, Seki N, Yano K, et al. Isolation and chromosomal assignment of a human gene encoding protein inhibitor of activated STAT3 (PIAS3). J Hum Genet. 1999; 44 (3):193~196.
    [18]Kotaja N, Karvonen U, Janne OA, et al. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol. Cell. Biol. 2002; 22 (14): 5222~5234.
    [19]Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000; 14 (2), 121~141.
    [20]Minty A, Dumont X, Kaghad M et al. Covalent modification of p73αby SUMO-1.Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. J. Biol. Chem. 2000; 275 (46), 36316~36323.
    [21]Duval D, Duval G, Kedinger C, et al. The‘PINIT’motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L. FEBS Lett. 2003; 554 (1-2), 111~118.
    [22]Wang L, Banejee S. Differential PIAS3 expression in human malignancy. Oncology Reports. 2004; 11 (6): 1319~1324.
    [23]Takeda K,Clausen BE,Kaisho T,et al.Enhanced Thl activity and development of chronic enterocolitis in mice devoid of STAT3 in macrophages and neutrophils[J].Immunity,1999,10:39-49
    [24]Chakraborty A,Dyer KF,Cascio M,et al.Identification of a novel STAT3 recruitment and activation motif within the G-CSFR[J].Blood,1999,93:15-24
    [25]Chakraborty A,Tweardy DJ.STAT3 and G-CSF-induced myeloid differenti-ation[J].Leuk lymphoma,1998,30:433-442
    [26]Hoey T,Grusby MJ.STATs as mediators of cytokine-induced response[J].Adv Immunol,1998,71:145-160
    [27]Liu B,Liao JY,Rao XP,et al Inhibition of STAT1-mediated gene activation by PIAS1.ProcNatl Acad Sci USA,1998,95:10626-10631
    [28]Chung CD,Liao J,Liu B, et al Specific Inhibition of STAT3 Signal transduction byPIAS3.Science,1997,278:1803-1805
    [29]Wible BA,Yang Q,Kuryshev YA,et al Cloning and expression of a novel K + channel regulatory protein,KChAP.J Biol Chem,1998,273(19):11745-11751
    [30]Wible BA,Wang L,Kuryshey YA,et al Increased K + efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3βin prostate cancer cells. J Biol Chem. 2002,277(20):17852-17862
    [31]Wang L, Banerjee S.Differential PIAS3 expression in human malignancy. Oncol Rep,2004,11(6):1319-1324
    [32]Long J,Wang G,Matsuura I,et al Activation of SMAD transcriptional activity by protein inhibitor of activated STAT3 (PIAS3).Proc Natl Acad Sci USA,2004, 101:99-104
    [33]Chakraborty A,Dyer KF,Cascio M,et al.Identification of a novel STAT3 recruitment and activation motif within the G-CSFR[J].Blood,1999,93:15-24
    [34]Ni Z,Lou W,Leman ES,et al.Inhibition of constitutively activatedSTAT3 signaling pathway suppresses growth of prostate cancer cells[J].Cancer Res,2000,60:1225-1228
    [35]Demoulin JB,van Roost E,Steven M,et al.Distinct roles for STAT1、STAT3 and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9[J].J Biol Chem,1999,274:25855-25861
    [36]Bromberg JF,Wrzeszczynska MH,Devan G,et al. STAT3 as an onco-gene[J]. Cell,1999,6;98(3):295-303.
    [37]Itoh M,Murata T,Suzuki T,et al. Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells [J].Oncogene,2006,23;25(8):1195-1204.
    [38]Niu G,Wright KL,Huang M,et al. Constitutive Stat3 activity up -regulates VEGF expression and tumor angiogenesis [J]. Oncogene,2002,27;21(13):2000-2008.
    [39]Grandis JR,Drenning SD,Zeng Q,et al. Constitutive activation of STAT3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo[J].Proc Natl Acad Sci USA,2000,11;97(8):4227-4232.
    [40]Leong PL,Andrews GA,Johnson DE,et al. Targeted inhibition of Stat3 with a decoy abrogates head and neck cancer cell growth[J]. Proc Natl Acad Sci USA,2003,1;100(7):4138-4143.
    [41]De Araujo VC,Furuse C,Cury PR,et al. STAT3 expression in salivary gland tumours[J]. Oral Oncol 2008,44(5):439-445.
    [42]Ueki N, Seki N, Yano K, et al. Isolation and chromosomal assignment of a human geneencoding protein inhibitor of activated STAT3 (PIAS3). J Hum Genet. 1999; 44 (3):193~196.
    [43]WangL, Banerjee S.DifferentialPIAS3 expression in human malignancy[J]. OncolRep, 2004, 11(6): 1319-1324.
    [44]纪华,王东林. PIAS3在人脑胶质瘤中的表达[J].第三军医大学学报, 2007, 29(12): 1240-1242.
    [45]Whittaker SR, Walton MI, Garrett MD, et al. The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res.2004, 64 (1):262~272.
    [46]Ogata Y, Osaki T, Naka T,et al Overexpression of PIAS3 suppresses cell growth and restores drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.Neoplasia,2006,8(10):817-825
    [47]Wible BA,Yang Q,Kuryshev YA,et al Cloning and expression of a novel K + channel regulatory protein,KChAP.J Biol Chem,1998,273(19):11745-11751
    [48]Cheng J,Zhang D,Zhou C,et al Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+T-Cells.Leuk Res,2004,28(1):71-82
    [1] Frank SJ,GillilandG,KraftAS, eta.l Interaction of the growth hormone receptor cytoplasmic domain with the JAK2 tyrosine kinase [J]. Endocrinology, 135: 2228-2239.
    [2] Fujitani Y, HibiM, Fukada T, et a.l An altemative pathway for STAT activation that ismediated by the direct interaction between JAK and STAT[J]. Oncogene, 1997, 14: 751-761.
    [3] Horvath CM,Darnell JE. The state of the STATs: recent develop-ments in the study of signal transduction to the nucleus[ J]. Cell Bio,l 1997, 9: 233-239.
    [4] Krebs DL,Hilton DJ. SOCS proteins: Negative regulators of cyto-kine signaling stem cells[J]. 2001, 19(5): 378-387.
    [5] Heinrich PC,Behrmann I,Muller Newen G,et al. Biochem J,1998,334:297-314.
    [6] Hou XS,Melnick MB,Perrimon N,et al. Cell,1996,84:411.
    [7] Yan R,Small S,Desplan C,et al. Cell,1996,84:421-430.
    [8] ShuaiK ,HorvathCM, HuangLH,et al.Interferon aetivation of the transcription factor State91 involves dimerization through SH2_phosphotyroslpeptide interactions[J].Cell,1994,76(5):821一828.
    [9] Levy D E. Physiological significance of STAT proteins:investigations through germ disruption in vivo[J],Cell Mol Izfe Sci,1999,55(21):1559_1567
    [10] Mui A L The role of STATS in proliferation,differentiation,and apoptosis[J],Cell Mol Life Sci,1999,55(12):1547_1558
    [11] Je Gailmeier, C SchaFer, P Moubarak. JAK and STAT proteins are exepressed and activeved by IFN-9 in rat pancreatic acinar cells [J]. CellularPhysio,l 2005, 203: 209-2161.
    [12] FukadaT,Ohtam T,YoshidaY, eta.l Stat3 or chestrates contradietory signals in cytokine-induced G1to S cell-cycle transition[J].EMBOJ, 1998, 17: 6670-66771.
    [13]胡欣,万大方. JAK/STAT信号转导途径研究进展及其与肿瘤的关系[J].肿瘤, 2005, 25(4): 4041.
    [14] CHUNG J,UCHID A E,GRAMMER T C,et al.STAT3 serine phosphorylation by ERK-dependent and-independent path-ways negatively modulates its tyrosine phosphorylation [J].Mol Cell Biol, 1997(17): 6508-6516.
    [15] CHAKRABORTY A,DYER K F,CASCIO M,et al.Identification of a novel STAT3 recruitment and activation motif with-in the granulocyte colony-stimulating factor receptor [J].Blood,1999,93(1):15-24.
    [16] LEEMAN R J,LUI V W, GRANDIS J R. STAT3 as a therapeutic target in head and neck cancer [J].Expert Opin Biol Ther,2006,6(3):231-241.
    [17] NIU G,WRIGHT K L,HUANG M,et al.Constitutive STAT Activity up-regulates VEGF expression and tumor angiogenesis [J].Oncogene,2002,21(13):2000-2008.
    [18] TURKSON J,BOWMAN T, GARCIA R,et al.Stat3 activation by Src induces specific gene regulation and is required for cell transformation [J]. Mol Cell Biol,1998,18:2545-2552.
    [19] HOSEA F H,THOMAS F M, PING S,et al.Stable expression of constitutively-activated STAT3 in benign prostatic epithelial cells changes their phenotype to that resembling malignant cells [J].Mol Cancer,2005,4(1):2-17.
    [20] NING Z Q,LI J,McGUINNESS M,et al.STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity [J].Oncogene,2001,20(33):4528-4536.
    [21] BENEKLI M, ZHENG X, KATHLEEN A,et al.Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival [J].Blood, 2002,99(1): 252-257.
    [22] EPLING-BURNETTE P K,LIU J H,CATLETT-FALCONER,et al.Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression [J]. J Clin Invest, 2001,107(3):351-362.
    [23] TAKEMOTO S,MULLOY J C,CERESETO A,et al.Proliferation of adult T cell leukemia Iymphoma cells is associated with the constitutive activation of JAK/STAT proteins [J].Proc Nati Acad Sci USA,1997(94):13897-13902.
    [24] FRANK D A,MAHAJAN S,RITZ J.B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription STAT1 and STAT3 constitutively phosphorylated on serine residues[J].JClin In-vest,1997,100:3140-3148.
    [25] Siavash H, Nikitakis NG, Sauk JJ. Br J Cancer, 2004,91(6):1074- 1080.
    [26] Kijima T, Niwa H, Steinman RA, et al. Cell GrowthDiffer, 2002, 13(8):355- 362.
    [27] HSIEH F C,CHENG G, LIN J,et al. Evaluation of potential Stat3-regulated genes in human breast cancer [J]. Biochem Biophys Res Commun,2005,335(2):292-299.
    [28] DOLLED-FILHART M,CAMP R L, KOWALSKI D P,et al. Tissue microarray analysis of signal transducers and activators of transcrip-tion 3 (Stat3) and phospho-Stat3 in node negative breast cancer shows nuclear localization is associated with a better prognosis[J]. Clin Cancer Res,2003,9:594-600.
    [29] DIEN J,AMIN H M, CHIU N,et al.Signal transducers and activators of transcription-3 up-regulates tissue inhibitor of metalloproteinase-1 expression and decreases invasiveness of breast cancer [J].Am J Pathol, 2006,169(2):633-642.
    [30] MA X T,WANG S, YE Y J,et al.Constitutive activation of Stat3signaling pathway in human colorectal carcinoma [J].World J Gastroenterol,2004,10(11):1569-1573.
    [31] KUSABA T, NAKAYAMA T, YAMAZUMI K,et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors [J].2005,58(8):833-838.
    [32] KAWADA M, SENO H, UENOYAMA Y, et al. Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of beta-catenin in colorectal cancer [J].Cancer Research,2006,66(6):2913-2917.
    [33] MORA L B, BUETTNER R, SEIGNE J,et al. Constitutive activation of Stat3 in human prostate tumors and cell lines:direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells [J] .Cancer Res,2002,62(22):6659-6666.
    [34] HORINAGA M,OKITA H,NAKASHIMA J,et al.Clinical and pathologic significance of activation of signal transducer and activator of transcription 3 in prostate cancer [J].Urology,2005,66(3):671-675.
    [35]胥文春,罗春丽,冯文莉,等.非小细胞肺癌组织中STAT3的表达及临床意义[J].临床检验杂志,2003,21(Suppl):23-24.
    [36] ERIC B H, ZHENG Z,SONG L X,et al. Activated epidermal growth factor receptor-Stat3 signaling promotes tumor survival in vivo in non-small cell lung cancer [J].Clin Cancer Res, 2005,11(23):8288-8294.
    [37] EndoTA,MasuharaM,YokouchiM, e ta 1.A new Protein containing an SH2 domain that inhibits JAK kinases.Nature,1997,387:921一924.
    [38] Naka T, Narazaki M, Hirata M, et al. Structure and function of a new STAT induced STAT inhibitor [J]. Nature, 1997,387:924- 929.
    [39] Liu B,Liao JY,Rao XP,et al Inhibition of STAT1-mediated gene activation by PIAS1.Proc Natl Acad Sci USA,1998,95:10626-10631
    [40] Chung CD,Liao J,Liu B, et al Specific Inhibition of STAT3 Signal transduction by PIAS3.Science,1997,278:1803-1805
    [41] ZhangQ,Raghunath PN,Xue L,et al.Multilevel dysregulation ofSTAT3 activation in anaplastic lymphoma kinase-positiveT/null-cell lymphoma[J]. Immunology, 2002, 168(1): 466-474.
    [42] YoshitakaO,TadashiO,TetsujiN,etal.Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3K/Akt inactivation[J].Neoplasia, 2006, 8(10): 817-825.
    [43] SchmidtD,MullerS. PIAS/SUMO: new partners in transcriptional regulation[J]. CellMolLife Sc,i 2003, 60(12): 2561-2574.
    [44] LiangM,MelchiorF,FengXH,etal.Regulation ofSmad4 sumoylation and transforming growth factor-βsignaling by protein inhibitor of activated STAT1 [ J]. Biol Chem, 2004, 279 (22): 22857 -22865.
    [45] Wible BA, Wang LM, Kuryshev YA, et al. Increased K+ efflux and apoptosis induced by the potassium channel modulatory protein KchAP/PIAS3B in prostate cancer cells. J Biol Chem, 2002, 277(20): 17852–17862.
    [46] Wang LM, Banerjee S. Differential PIAS3 expression in human malignancy. Oncology Reports, 2004, 11(6): 1319–1324.

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