摘要目的 探讨幽门螺杆菌(H. pylori)细胞毒素相关基因A(CagA)蛋白调控胃癌细胞上皮-间质转化(EMT)的作用机制。方法 以“幽门螺杆菌”、“细胞毒素相关基因A蛋白”、“胃癌细胞”、“上皮-间质转化”为关键词,在中国知网、万方数据库、Pubmed、 Web of Science检索1990年1月—2015年1月国内外关于CagA及EMT的文献,进行归纳总结。结果 CagA蛋白通过Ⅳ型分泌系统(T4SS)进入宿主细胞后,除了既往认为的可能参与胃黏膜上皮早期癌变的发生,还可与多种信号分子结合,通过调控基因转录水平(如上调Twist、Snail等与EMT相关的信号通路分子)、上调相关miRNA(如miRNA-584、miRNA-1290等)来降解或阻遏目标mRNA等不同途径来调控细胞的生长和运动相关的信号通路,导致胃癌细胞EMT的发生。结论 CagA可通过不同的途径调控胃黏膜上皮细胞发生EMT。对这些途径及其机制的全面且进一步的研究将有助于对胃癌浸润和转移的机理的了解。
Abstract：Objective To explore the progress of cytotoxin-associated gene A (CagA) protein in the regulation of EMT(epithelial-mesenchymal transition) in gastric cancer cells.Methods To review and summarize the domestic and foreign references related to CagA and EMT from CNKI, Wanfang database, Pubmed and Web of Science from January 1990 to January 2015, the keywords of “Helicobacter pylori”, “CagA”, “gastric cancer cells”, “epithelial-mesenchymal transition” in either English or Chinese were used.Results CgaA protein is delivered into epithelial cells via a type Ⅳ secretion system. In this process, CagA is not only associated with early gastric cancer, but also binds to and activates/inactivates multiple signaling proteins, regulates different pathways included up-regulation of EMT-related transcription factors (Twist, Snail) , repression of targeted mRNA by up-regulate miRNA related to growth and motility (miRNA-584, miRNA-1290, etc.), leads to EMT in gastric cancer cells.Conlusions CagA may result in EMT in gastric cancer cells with different pathways. Comprehensive research of these pathways will be beneficial for understanding the mechanism of invasion and metastasis of gastric cancer.
王喆, 王志荣. 幽门螺杆菌细胞毒素相关基因A蛋白调控胃癌细胞上皮-间质转化的研究进展[J]. 中华解剖与临床杂志, 2015, 20(2): 170-173.
Wang Zhe, Wang Zhirong. Research progress of cytotoxin-associated gene A protein in the regulation of epithelial-mesenchymal transition in gastric cancer cells. Chinese Journal of Anatomy and Clinics, 2015, 20(2): 170-173.
Malfertheiner P, Megraud F, O′Morain CA, et al. Management of Helicobacter pylori infection--the Maastricht Ⅳ/Florence Consenus Report[J]. Gut, 2012, 61(5): 646-664.
[2]
Yamaoka Y. Pathogenesis of Helicobacter pylori-related gastroduodenal diseases from molecular epidemiological studies[J]. Gastroenterol Res Pract, 2012, 2012: 371503.
[3]
Ricci V, Romano M, Boquet P. Molecular cross-talk between Helicobacter pylori and human gastric mucosa[J]. World J Gastroenterol, 2011, 17(11): 1383-1399.
[4]
Murata-Kamiya N, Kikuchi K, Hayashi T, et al. Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein[J]. Cell Host Microbe, 2010, 7(5): 399-411.
[5]
Hayashi T, Senda M, Morohashi H, et al. Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA[J]. Cell Host Microbe, 2012, 12(1): 20-33.
[6]
Mueller D, Tegtmeyer N, Brandt S, et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains[J]. J Clin Invest, 2012, 122(4): 1553-1566.
[7]
Sibony M, Jones NL. Recent advances in Helicobacter pylori Pathogenesis[J]. Curr Opin Gastroenterol, 2012, 28(1): 30-35.
[8]
Wessler S, Backert S. Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori[J]. Trends Microbiol, 2008, 16(8): 397-405.
[9]
Suzuki M, Mimuro H, Suzuki T, et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion[J]. J Exp Med, 2005, 202(9): 1235-1247.
[10]
Churin Y, Al-Ghoul L, Kepp O, et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhance the motogenic response[J]. J Cell Biol, 2003, 161(2): 249-255.
[11]
Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis[J]. J Am Soc Nephrol, 2010, 21(2): 212-222.
[12]
Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression[J]. J Mammary Gland Biol Neoplasia, 2010, 15(2): 117-134.
[13]
Gabbert HE, Mueller W, Schneiders A, et al. Prognostic value of E-cadherin expression in 413 gastric carcinomas[J]. Int J Cancer, 1996, 69(3): 184-189.
[14]
Feng MY, Wang K, Shi QT, et a1.Gene expression profiling in TWIST-depleted gastric cancer cells[J]. Anat Rec(Hoboken), 2009, 292(2): 262-270.
[15]
Yang Z, Zhang X, Gang H, et a1. Up-regulation of gastric cancer cell invasion by Twit is accompanied by N-cadherin and fibronectin expression[J] Biochem Biophys Res Commun, 2007, 358(3): 925-930.
[16]
Dai YH, Tang YP, Zhu HY, et al. ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells[J]. Dig Dis Sci, 2012, 57(5): 1253-1260.
[17]
Okugawa Y, Toiyama Y, Tanaka K, et al. Clinical significance of zinc finger E-box binding homeobox 1 (ZEB1) in human gastric cancer[J]. J Surg Oncol, 2012, 106(3): 280-285.
[18]
Otsuki S, Inokuchi M, Enjoji M, et al. Vimentin expression is associated with decreased survival in gastric cancer[J]. Oncol Rep, 2011, 25(5): 1235-1242.
[19]
Ru GQ, Wang HJ, Xu WJ, et al. Upregulation of Twist in gastric carcinoma associated with tumor invasion and poor prognosis[J]. Pathol Oncol Res, 2011, 17(2): 341-347.
[20]
Segal ED, Cha J, Lo J, et al. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes in Helicobacter pylori[J]. Proc Natl Acad Sci USA, 1999, 96(25): 14559-14564.
[21]
Bagnoli F, Buti L, Tompkins L, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells[J]. Proc Natl Acad Sci USA, 2005, 102(45): 16339-16344.
[22]
Saito Y, Murata-Kamiya N, Hirayama T, et al. Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21[J]. J Exp Med, 2010, 207(10): 2157-2174.
[23]
Sohn SH, Lee YC. The genome-wide expression profile of gastric epithelial cells infected by naturally occurring cagA isogenic strains of Helicobacter pylori[J]. Environ Toxicol Pharmacol, 2011, 32(3): 382-389.
[24]
Yu H, Zeng J, Liang X, et al. Helicobacter pylori Promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4)[J]. PLoS One, 2014, 9(8): e105306.
[25]
Yang HS, Matthews CP, Clair T, et al. Tumourigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion[J]. Mol Cell Biol, 2006, 26(4): 1297-1306.
[26]
Suzuki M, Mimuro H, Kiga K, et al. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation[J]. Cell Host Microbe, 2009, 5(1): 23-34.
[27]
Smith JP, Pozzi A, Dhawan P, et al. Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2[J]. Am J Physiol Renal Physiol, 2009, 296(5): F957-965.
[28]
Yin Y, Grabowska AM, Clarke PA, et al. Helicobacter pylori potentiates epithelial: mesenchymal transitionin gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7[J]. Gut, 2010, 59(8): 1037-1045.
[29]
Lee YS, Lee do Y, Yu da Y, et al. Helicobacter pylori Induces cell migration and invasion through casein kinase 2 in gastric epithelial cells[J]. Helicobacter, 2014, 19(6): 465-475.
[30]
Lee DG, Kim HS, Lee YS, et al. Helicobacter pylori CagA promotes snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity[J]. Nat Commun, 2014, 5: 4423
[31]
Zhu Y, Jiang Q, Lou X, et al. MicroRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells[J]. PloS One, 2012, 7(4): e35147.
[32]
Zhou X, Li L, Su J, et al. Decreased miR-204 in H. pylori-associated gastric cancer promotes cancer cell proliferation and invasion by targeting SOX4[J]. PloS One, 2014, 9(7): e101457.
[33]
Baud J, Varon C, Chabas S, et al. Helicobacter pylori initiates a mesenchymal transition through ZEB1 in gastric epithelial cells[J]. PloS One, 2013, 8(4): e60315.
[34]
Kang MH, Kim JS, Seo JE, et al. BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation ofthe phosphatidylinositol 3-kinase (P13K)/Akt pathway[J]. Exp Cell Res, 2010, 316(1): 24-37.
[35]
Yoo YA, Kang MH, Lee HJ, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT and MMP-9 pathway in gastric cancer[J]. Cancer Res, 2011, 71(22): 7061-7070.
[36]
Nagy TA, Frey MR, Yan F, et a1. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling[J]. J Infect Dis, 2009, 199(5): 641-651.
2015, Vol. 20 
