张遥;任秀智;韩金祥;鲁艳芹;

• 1:山东省罕少见病重点实验室山东省医药生物技术研究中心山东省医学科学院
• 2:济南大学-山东省医学科学院医学与生命科学学院
• 3:天津市武清区人民医院

摘要(Abstract)：

Wnt信号传导通路是一条广泛存在于多细胞生物体内且具有高度进化保守性的信号通路。该通路对细胞增殖、分化、凋亡、细胞极性及细胞的迁移和侵入产生影响,在多种器官的发育形成过程以及成体状态下病理生理过程中发挥重要作用。目前已有大量研究表明,Wnt信号通路的改变与肿瘤的形成和发生、退行性疾病的发展以及干细胞功能的改变密切相关。有更多新的研究表明,该通路与炎症发生、新生血管形成、免疫功能的维持以及创伤愈合和组织再生也有潜在性的联系。该通路正作为一个关键热点应用于上述各个领域的基础应用及药物开发研究中。本文在检索Pub Med上关于Wnt信号通路与人类疾病文献的基础上,从Wnt信号通路的组成及其与人类纤维化疾病、代谢综合征、眼部疾病、肿瘤和骨相关疾病等方面的相关性,阐明Wnt信号传导通路在细胞的增殖、分化、凋亡等过程中发挥的重要调节作用及对维持诸多器官的正常发育和形成所起的至关重要的作用。

关键词(KeyWords)： Wnt信号通路;纤维化疾病;代谢综合征;肿瘤;骨相关疾病

Abstract:

Keywords:

基金项目(Foundation): 山东省英才基金项目(2015ZRC03171);; 山东省国际科技合作项目资助

作者(Authors): 张遥;任秀智;韩金祥;鲁艳芹;

参考文献(References)：

• [1]ZHANG P,CAI Y,SOOFI A,et al.Activation of Wnt11 by transforming growth factor-βdrives mesenchymal gene expression through non-canonical Wnt protein signaling in renal epithelial cells[J].J Biol Chem,2012,287(25):21290-21302.
• [2]MAZZOTTA S,NEVES C,BONNER R J,et al.Distinctive roles of canonical and noncanonical Wnt signaling in human embryonic cardiomyocyte development[J].Stem Cell Reports,2016,7(4):764-776.
• [3]RAO T P,K譈HL M.An updated overview on Wnt signaling pathways:a prelude for more[J].Circ Res,2010,106(12):1798-1806.
• [4]SCHUIJERS J,MOKRY M,HATZIS P,et al.Wnt-induced transcriptional activation is exclusively mediated by TCF/LEF[J].EMBO J,2014,33(2):146-156.
• [5]ASHOURI S,KHUJIN M H,KAZEMI M,et al.Effect of teicoplanin on the expression of c-myc and c-fos proto-oncogenes in MCF-7 breast cancer cell line[J].Adv Biomed Res,2016,5:172-175.
• [6]HASSANIAN S M,ARDESHIRYLAJIMI A,DINARVAND P,et al.Inorganic polyphosphate promotes cyclin D1 synthesis through activation of m TOR/Wnt/β-catenin signaling in endothelial cells[J].J Thromb Haemost,2016,14(11):2261-2273.
• [7]MADAN B,KE Z,LEI Z D,et al.NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition[J].Oncotarget,2016,7(11):12386-12392.
• [8]QIU C Z,WANG M Z,YU W S,et al.Correlation of GOLPH3gene with Wnt signaling pathway in human colon cancer cells[J].J Cancer,2016,7(8):928-934.
• [9]L譈DTKE T H,RUDAT C,WOJAHN I,et al.Tbx2 and Tbx3act downstream of Shh to maintain canonical Wnt signaling during branching morphogenesis of the murine lung[J].Dev Cell,2016,39(2):239-253.
• [10]BERNKOPF D B,HADJIHANNAS M V,BEHRENS J.Negative-feedback regulation of the Wnt pathway by conductin/axin2 involves insensitivity to upstream signalling[J].J Cell Sci,2015,128(1):33-39.
• [11]OVEJERO C,CAVARD C,P魪RIANIN A,et al.Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene ofβ-catenin in the liver[J].Hepatology,2004,40(1):167-176.
• [12]ZHOU F Q,QI Y M,XU H,et al.Expression of Ep CAM and Wnt/β-catenin in human colon cancer[J].Genet Mol Res,2015,14(2):4485-4494.
• [13]R魻NSCH K,J魧GER M,SCH魻PFLIN A,et al.Class I and IIIHDACs and loss of active chromatin features contribute to epigenetic silencing of CDX1 and EPHB tumor suppressor genes in colorectal cancer[J].Epigenetics,2011,6(5):610-622.
• [14]YANG J,ZHANG K,WU J,et al.Wnt5a increases properties of lung cancer stem cells and resistance to cisplatin through activation of Wnt5a/PKC signaling pathway[J].Stem Cells Int,2016,2016:1690896.
• [15]CIZELSKY W,TATA A,K譈HL M,et al.The Wnt/JNKsignaling target gene alcam is required for embryonic kidney development[J].Development,2014,141(10):2064-2074.
• [16]CERPA W,LATORRE-ESTEVES E,BARRIA A.Ro R2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission[J].Proc Natl Acad Sci USA,2015,112(15):4797-4802.
• [17]LIU S,LIU Y P,HUANG Z J,et al.Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats[J].Pain,2015,156(12):2572-2584.
• [18]LIU S S,ZHOU P,ZHANG Y.Abnormal expression of key genes and proteins in the canonical Wnt/β-catenin pathway of articular cartilage in a rat model of exercise-induced osteoarthritis[J].Mol Med Rep,2016,13(3):1999-2006.
• [19]KIM T H,KIM S H,SEO J Y,et al.Blockade of the Wnt/beta-catenin pathway attenuates bleomycin-induced pulmonary fibrosis[J].Tohoku J Exp Med,2011,223(1):45-54.
• [20]CHEN Y,HUANG Q,ZHOU H,et al.Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide(LEF)-mediated cytotoxic effects on renal carcinoma cells[J].Oncotarget,2016,7(31):50401-50416.
• [21]HINO M,KAMO M,SAITO D,et al.Transforming growth factor-β1 induces invasion ability of HSC-4 human oral squamous cell carcinoma cells through the Slug/Wnt-5b/MMP-10 signalling axis[J].J Biochem,2016,159(6):631-640.
• [22]KAWAKAMI T,REN S,DUFFIELD J S.Wnt signalling in kidney diseases:dual roles in renal injury and repair[J].JPathol,2013,229(2):221-231.
• [23]DUAN J,GHERGHE C,LIU D,et al.Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair[J].EMBO J,2012,31(2):429-442.
• [24]SCHINNER S.Wingless-type MMTV integration site family(WNT)signalling in pancreatic beta cells-more complex than expected[J].Diabetologia,2010,53(9):2073-2075.
• [25]ESTEVE P,BOVOLENTA P.Secreted inducers in vertebrate eye development:more functions for old morphogens[J].Curr Opin Neurobiol,2006,16(1):13-19.
• [26]MUKHOPADHYAY M,GORIVODSKY M,SHTROM S,et al.Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium[J].Development,2006,133(11):2149-2154.
• [27]CHEN Y,STUMP R J,LOVICU F J,et al.A role for Wnt/planar cell polarity signaling during lens fiber cell differentiation[J].Semi Cell Dev Biol,2006,17(6):712-725.
• [28]WANG Z,CHENG R,LEE K,et al.Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization[J].Arterioscler Thromb Vasc Biol,2015,35(4):855-864.
• [29]DEAN C H,MILLER L A,SMITH A N,et al.Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland[J].Dev Biol,2005,286(1):270-286.
• [30]GOKSEL G,BILIR A,USLU R,et al.WNT1 gene expression alters in heterogeneous population of prostate cancer cells;decreased expression pattern observed in CD133+/CD44+prostate cancer stem cell spheroids[J].J BUON,2014,19(1):207-214.
• [31]BELL E,MU譙OZ-SANJU魣N I,ALTMANN C R,et al.Cell fate specification and competence by Coco,a maternal BMP,TGFbeta and Wnt inhibitor[J].Development,2003,130(7):1381-1389.
• [32]ASEM M S,BUECHLER S,WATES R B,et al.Wnt5a signaling in cancer[J].Cancers(Basel),2016,8(9):pii:E79.doi:10.3390/cancers8090079.
• [33]B魣NYAI L,PATTHY L.The NTR module:domains of netrins,secreted frizzled related proteins,and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases[J].Protein Sci,1999,8(8):1636-1642.
• [34]FENG W,YANG C X,ZHANG L,et al.Curcumin promotes the apoptosis of human endometrial carcinoma cells by downregulating the expression of androgen receptor through Wnt signal pathway[J].Eur J Gynaecol Oncol,2014,35(6):718-723.
• [35]BUI T D,O'BRIEN T,CREW J,et al.High expression of Wnt7b in human superficial bladder cancer vs invasive bladder cancer[J].Br J Cancer,1998,77(2):319-324.
• [36]XIAO X,XIAO Y,WEN R,et al.Promoting roles of the secreted frizzled-related protein 2 as a Wnt agonist in lung cancer cells[J].Oncol Rep,2015,34(5):2259-2266.
• [37]NIU L J,XU R X,ZHANG P,et al.Suppression of Frizzled-2-mediated Wnt/Ca2+signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury[J].Neuroscience,2012,213(6):19-28.
• [38]ZOU H,HENZEL W J,LIU X,et al.Apaf-1,a human protein homologous to C.elegans CED-4,participates in cytochrome c-dependent activation of caspase-3[J].Cell,1997,90(3):405-413.
• [39]LI H,HAN J X,LU Y Q.Advances in pathology of osteogenesis imperfecta[J].Chin J Pathol,2013,42(11):780-783.(in Chinese)李虎,韩金祥,鲁艳芹.成骨不全的病理学研究进展[J].中华病理学杂志,2013,42(11):780-783.
• [40]LU Y Q,REN X Z,WANG Y Z,et al.Molecular mechanisms of osteogenesis imperfecta[J].Prog in Biochem Biophys,2015,42(6):511-518.(in Chinese)鲁艳芹,任秀智,王延宙,等.成骨不全及其分子机制[J].生物化学与生物物理进展,2015,42(6):511-518.
• [41]XU C,HAN J X,LU Y Q.Molecular mechanism of osteogenesis imperfecta[J].Chin J Biochem Mol Biol,2012,28(4):310-315.(in Chinese)徐超,韩金祥,鲁艳芹.成骨不全的分子机制[J].中国生物化学与分子生物学报,2012,28(4):310-315.
• [42]NIZIOLEK P J,BULLOCK W,WARMAN M L,et al.Missense mutations in LRP5 associated with high bone mass protect the mouse skeleton from disuse-and ovariectomy-induced osteopenia[J].PLo S One,2015,10(11):e0140775.doi:10.1371/journal.pone.0140775.
• [43]KORVALA J,L魻IJA M,M魧KITIE O,et al.Rare variations in WNT3A and DKK1 may predispose carriers to primary osteoporosis[J].Eur J Med Genet,2012,55(10):515-519.
• [44]LU Y,REN X,WANG Y,et al.Mutational and structural characteristics of four novel heterozygous C-propeptide mutations in the proα1(I)collagen gene in Chinese osteogenesis imperfecta patients[J].Clin Endocrinol(Oxf),2014,80(4):524-531.
• [45]ALMARIO R U,KARAKAS S E.Roles of circulating WNT-signaling proteins and WNT-inhibitors in human adiposity,insulin resistance,insulin secretion,and inflammation[J].Horm Metab Res,2015,47(2):152-157.
• [46]GIAKOUSTIDIS A,GIAKOUSTIDIS D,MUDAN S,et al.Molecular signalling in hepatocellular carcinoma:Role of and crosstalk among WNT/β-catenin,Sonic Hedgehog,Notch and Dickkopf-1[J].Can J Gastroenterol Hepatol,2015,29(4):209-217.
• [47]AURREKOETXEA M,IRASTORZA I,GARCIA-GALLASTE-GUI P,et al.Wnt/β-catenin regulates the activity of epiprofin/Sp6,SHH,FGF,and BMP to coordinate the stages of odontogenesis[J].Front Cell Dev Biol,2016,4:25.
• [48]ZHOU T,HU Y,CHEN Y,et al.The pathogenic role of the canonical Wnt pathway in age-related macular degeneration[J].Invest Ophthalmol Vis Sci,2010,51(9):4371-4379.