DKK1与牙齿发育和口腔疾病关系的研究进展
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摘要
Dickkopf家族(DKK)是进化中高度保守的古老体系,通过抑制Wnt通路的信号传导来发挥调节作用。DKK1作为DKK家族的重要成员具有广泛的生物学功能,可以通过调节细胞生长、迁移、分化来控制机体发育和疾病发展,在胚胎发育和肿瘤形成等方面研究较为成熟。随着近年来人们对口腔健康的重视和一些口腔疾病发病率逐年上涨,学者们对疾病的分子机制领域研究逐渐深入,DKK1通过调节Wnt通路这一重要机制在口腔医学领域也逐渐得到重视,并被认为是一个潜在的肿瘤治疗靶点。本文通过综述近年来国内外学者对DKK1在牙齿发育和口腔的常见疾病如口腔肿瘤、口腔黏膜下纤维化等方面的研究成果,分析其中可能的分子机制,为学者们未来进一步研究牙齿形态发育的精密调控机制和口腔疾病的防治提供理论参考与思路。
The Dickkopf family(DKK)is a highly conserved ancient system during evolution,which has effects of regulation on inhibiting the signal transduction of the Wnt pathway. As a key member of the DKK family,DKK1 has a wide range of biological functions. It controls the growth and the progress of disease through regulating cell proliferation,migration and differentiation. There were wide range of studies on the embryonic development and tumorigenesis. With an increasing awareness of the importance of oral health and an increase in the incidence of some oral diseases,the molecular mechanisms of diseases have been investigated gradually. The fact that DKK1 regulates Wnt pathway has gradually gained attention in oral medicine,and it is thought to be a potential cancer treatment target. In recent years,scholars have discovered that DKK1 attracts attention by regulating cell growth, migration, and differentiation to affect the development of oral organs and the occurrence of oral diseases. In this paper,we reviewed the recent studies on the effects of DKK1 on tooth development and common oral diseases such as oral tumor and oral submucous fibrosis,and also analyzed the possible molecular mechanism. This review would provide a theoretical basis for the further investigation of the regulatory mechanism of tooth development and DKK1-targeting therapeutic strategies for oral diseases.
The Dickkopf family(DKK)is a highly conserved ancient system during evolution,which has effects of regulation on inhibiting the signal transduction of the Wnt pathway. As a key member of the DKK family,DKK1 has a wide range of biological functions. It controls the growth and the progress of disease through regulating cell proliferation,migration and differentiation. There were wide range of studies on the embryonic development and tumorigenesis. With an increasing awareness of the importance of oral health and an increase in the incidence of some oral diseases,the molecular mechanisms of diseases have been investigated gradually. The fact that DKK1 regulates Wnt pathway has gradually gained attention in oral medicine,and it is thought to be a potential cancer treatment target. In recent years,scholars have discovered that DKK1 attracts attention by regulating cell growth, migration, and differentiation to affect the development of oral organs and the occurrence of oral diseases. In this paper,we reviewed the recent studies on the effects of DKK1 on tooth development and common oral diseases such as oral tumor and oral submucous fibrosis,and also analyzed the possible molecular mechanism. This review would provide a theoretical basis for the further investigation of the regulatory mechanism of tooth development and DKK1-targeting therapeutic strategies for oral diseases.
引文
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[28]Chen L,Li M,Li Q,et al.DKK1 promotes hepatocellular carcinoma cell migration and invasion throughβ-catenin/MMP7signaling pathway[J].Mol Cancer,2013(12):157.
[29]Cui H,Li H,Li QL,et al.Dickkopf-1 induces apoptosis in the JEG3 and Be Wo trophoblast tumor cell lines through the mitochondrial apoptosis pathway[J].Int J Oncol,2015,46(6):2555-2561.
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[33]Tilakaratne WM,Klinikowski MF,Saku T,et al.Oral submucous fibrosis:review on aetiology and pathogenesis[J].Oral Oncol,2006,42(6):561-568.
[34]王燕平,贺琪,吴飞,等.Wnt3a对肝星状细胞增殖活化以及转化生长因子β/Smad表达的影响[J].中华肝脏病杂志,2013,21(2):111-115.
[35]Brack AS,Conboy MJ,Roy S,et al.Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis[J].Science,2007,317(5839):807-810.
[36]Sato M.Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids[J].Acta Derm Venereol,2006,86(4):300-307.
[37]Zhou S,Zhu Y,Mashrah M,et al.Expression pattern of DKK3,dickkopf WNT signaling pathway inhibitor 3,in the malignant progression of oral submucous fibrosis[J].Oncol Rep,2017,37(2):979-985.
[38]Zhou S,Chen L,Mashrah M,et al.Deregulation of secreted frizzled-related proteins is associated with aberrantβ-catenin activation in the carcinogenesis of oral submucous fibrosis[J].Onco Targets Ther,2015(8):2923-2931.
[2]Glinka A,Wu W,Delius H,et al.Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction[J].Nature,1998,391(6665):357-362.
[3]李冬梅,许春姣.DKK1基因及其基因多态性与口腔疾病的关系研究进展[J].中国实用口腔科杂志,2017,10(3):175-179.
[4]Mao B,Wu W,Davidson G,et al.Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signaling[J].Nature,2002,417(6889):664-667.
[5]Mao B,Wu W,Li Y,et al.LDL-receptor-related protein 6 is a receptor for Dickkopf proteins[J].Nature,2001,411(6835):321-325.
[6]Klaus A,Birchmeier W.Wnt signalling and its impact on development and cancer[J].Nat Rev Cancer,2008,8(5):387-398.
[7]Kolligs FT,Bomme G,G?ke B.Wnt/beta-catenin/tcf signaling:a critical pathway in gastrointestinal tumorigenesis[J].Digestion,2002,66(3):131-144.
[8]Price MA.CKI,there′s more than one:casein kinase I family members in Wnt and Hedgehog signaling[J].Genes Dev,2006,20(4):399-410.
[9]Saito-Diaz K,Chen TW,Wang X,et al.The way Wnt works:components and mechanism[J].Growth Factors,2013,31(1):1-31.
[10]Tucker A,Sharpe P.The cutting-edge of mammalian development;how the embryo makes teeth[J].Nat Rev Genet,2004,5(7):499-508.
[11]Holstein TW.The evolution of the Wnt pathway[J].Cold Spring Harbor Perspect Biol,2012,4(7):a007922.
[12]Liu F,Chu EY,Watt B,et al.Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis[J].Dev Biol,2008,313(1):210-224.
[13]Wang B,Li H,Liu Y,et al.Expression patterns of WNT/β-CATENIN signaling molecules during human tooth development[J].J Mol Histol,2014,45(5):487-496.
[14]Han XL,Liu M,Voisey A,et al.Post-natal effect of overexpressed DKK1 on mandibular molar formation[J].J Dent Res,2011,90(11):1312-1317.
[15]Luo J,Chen J,Deng ZL,et al.Wnt signaling and human diseases:what are the therapeutic implications[J].Lab Invest,2007,87(2):97-103.
[16]Clevers H.Wnt/beta-catenin signaling in development and disease[J].Cell,2006,127(3):469-480.
[17]Tian E,Zhan FH,Walker R,et al.The role of the WntSignaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma[J].N Engl J Med,2003,349(26):2483-2494.
[18]Wirths O,Waha A,Weggen S,et al.Overexpression of human Dickkopf-1,an antagonist of wingless/WNT signaling,in human hepatoblastomas and Wilms′tumors[J].Lab Invest,2003,83(3):429-434.
[19]Patil MA,Chua MS,Pan KH,et al.An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma[J].Oncogene,2005,24(23):3737-3747.
[20]Gonzalex-Sancho JM,Aguilera O,Garcia JM,et al.The Wnt antagonist DICKKOPF-1 gene is a downstream target of betacatenin/TCF and is downregulated in human colon cancer[J].Oncogene,2005,24(6):1098-1103.
[21]Gao C,Xie R,Ren C,et al.Dickkopf-1 expression is a novel prognostic marker for gastric cancer[J].J Biomed Biotechnol,2012,2012(1):804592.
[22]Li S,Qin X,Xin G,et al.Dickkopf-1 Is Oncogenic and involved in invasive growth in non small cell lung cancer[J].PLo S One,2013,8(12):e84944.
[23]Kyvernitakis I,Rachner TD,Urbschat A,et al.Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1,bone turnover markers and bone mineral density in women with breast cancer[J].J Cancer Res Clin Oncol,2014,140(10):1671-1680.
[24]Mikheev AM,Mikheeva SA,Maxwell JP,et al.Dickkopf-1mediated tumor suppression in human breast carcinoma cells[J].Breast Cancer Res Treat,2008,112(2):263-273.
[25]Ogoshi K,Kasamatsu A,Iyoda M,et al.Dickkopf-1 in human oral cancer[J].Int J Oncol,2011,39(2):329-336.
[26]Iwai S,Yonekawa A,Harada C,et al.Involvement of the Wnt-β-catenin pathway in invasion and migration of oral squamous carcinoma cells[J].Int J Oncol,2010,37(5):1095-1103.
[27]Weng J,Zhang H,Wang C,et al.mi R-373-3p Targets DKK1 to Promote EMT-Induced Metastasis via the Wnt/β-Catenin Pathway in Tongue Squamous Cell Carcinoma[J].Biomed Res Int,2017(2017):6010926.
[28]Chen L,Li M,Li Q,et al.DKK1 promotes hepatocellular carcinoma cell migration and invasion throughβ-catenin/MMP7signaling pathway[J].Mol Cancer,2013(12):157.
[29]Cui H,Li H,Li QL,et al.Dickkopf-1 induces apoptosis in the JEG3 and Be Wo trophoblast tumor cell lines through the mitochondrial apoptosis pathway[J].Int J Oncol,2015,46(6):2555-2561.
[30]张卫民,高岩.Wnt信号传导通路组成蛋白与口腔鳞状细胞癌的分化和增殖[J].中华口腔医学杂志,2005,40(6):491-494.
[31]Han SX,Zhou X,Sui X,et al.Serum dickkopf-1 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer[J].Oncotarget,2015,6(23):19907-19917.
[32]Paluszczak J,Sarbak J,Kostrzewska-Poczekaj M,et al.The negative regulators of Wnt pathway-DACH1,DKK1,and WIF1are methylated in oral and oropharyngeal cancer and WIF1methylation predicts shorter survival[J].Tumor Biol,2015,36(4):2855-2861.
[33]Tilakaratne WM,Klinikowski MF,Saku T,et al.Oral submucous fibrosis:review on aetiology and pathogenesis[J].Oral Oncol,2006,42(6):561-568.
[34]王燕平,贺琪,吴飞,等.Wnt3a对肝星状细胞增殖活化以及转化生长因子β/Smad表达的影响[J].中华肝脏病杂志,2013,21(2):111-115.
[35]Brack AS,Conboy MJ,Roy S,et al.Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis[J].Science,2007,317(5839):807-810.
[36]Sato M.Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids[J].Acta Derm Venereol,2006,86(4):300-307.
[37]Zhou S,Zhu Y,Mashrah M,et al.Expression pattern of DKK3,dickkopf WNT signaling pathway inhibitor 3,in the malignant progression of oral submucous fibrosis[J].Oncol Rep,2017,37(2):979-985.
[38]Zhou S,Chen L,Mashrah M,et al.Deregulation of secreted frizzled-related proteins is associated with aberrantβ-catenin activation in the carcinogenesis of oral submucous fibrosis[J].Onco Targets Ther,2015(8):2923-2931.