Advances in signal transduction pathway regulating EMT in tumor invasion and metastasis

doi:10.3760/cma.j.issn.1673-422X.2014.03.004

Abstract

Abstract: Epithelialmesenchymal transition (EMT) is a differentiation process of epithelial cells into mesenchymals, which is widespread in the invasion and metastasis of malignant tumor. Studies show that EMT is influenced by a variety of factors such as cytokines, signaling pathways and transcription factors. Studies also show that intracellular and extracellular signal transmission could induce EMT. Signal transduction is a process which involves ligandreceptor binding in the extracellular, going into the cell and activating different nuclear transduction factor through intracellular signal transduction pathway.

Key words: Neoplasm invasiveness, Neoplasm metastasis, Epithelialmesenchymal transition

ZHU Lei, SUI Hua, DENG Wan-Li. Advances in signal transduction pathway regulating EMT in tumor invasion and metastasis[J]. Journal of International Oncology, 2014, 41(3): 172-177.

References

［1］ Theiry JP, Acloque H, Huang RY, et al. Epithelialmesenchymal transitions in development and disease［J］. Cell, 2009, 139(5):871-890. ［2］ Liu Y. New insights into epithelialmesenchymal transition in kidney fibrosis［J］. J Am Soc Nephrol, 2010, 21(2):212-222. ［3］ LópezNovoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression［J］. EMBO Mol Med， 2009, 1(6-7):303-314. ［4］ Sun T, Zhao N, Zhao XL, et al. Expression and functional significance of twist1 in hepatocellular carcinoma:its role in vasculogenic mimicry［J］. Hepatology, 2010, 51(2):545-556. ［5］ Sabe H. Cancer early dissemination:cancerous epithelial mesenchymal transdifferentiation and transforming growth factor β signaling［J］. J Biochem, 2011, 149(6):633-639. ［6］ Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic［J］. Biochim Biophys Acta, 2009, 1796(2):75-90. ［7］ Meng X, Ezzati P, Wilkins JA. Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition［J］. PLoS One, 2011, 6(4):e18715. ［8］ Qiao B, Johnson NW, Gao J. Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-beta1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions［J］. Int J Oncol, 2010, 37(3):663-668. ［9］ Li QQ, Xu JD, Wang WJ, et al. Twist1-mediated Adriamycin-induced epithelialmesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells［J］. Clin Cancer Res， 2009, 15(8):2657-2665. ［10］ Rosanò L, Cianfrocca R, Spinella F, et al. Acquisition of chemoresistance and EMT phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells［J］. Clin Cancer Res， 2011, 17(8):2350-2360. ［11］ Davalos V, Moutinho C, Villanueva A, et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis［J］. Oncogene, 2012, 31(16):2062-2074. ［12］ Natalwala A, Spychal R, Tselepis C. Epithelial-mesenchyrreal transition mediated tumourigenesis in the gastrointestinal tract［J］. World J Gastroenterol, 2008, 14(24):3792-3797. ［13］ Ungefroren H, Groth S, Sebens S, et al. Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1［J］. Mol Cancer， 2011, 10:67. ［14］ Veerasamy M, Phanish M, Dockrell ME. Smad mediated regulation of inhibitor of DNA binding 2 and its role in phenotypic maintenance of human renal proximal tubule epithelial cells［J］. PLoS One, 2013, 8(1):e51842. ［15］ Chitalia V, Shivanna S, Martorell J, et al. cCbl, a ubiquitin E3 ligase that targets active β-catenin: a novel layer of Wnt signaling regulation［J］. J Biol Chem, 2013, 288(32):23505-23517. ［16］ Zhao JH, Luo Y, Jiang YG, et al. Knockdown of β-Catenin through shRNA cause a reversal of EMT and metastaic phenotypes induced by HIF-1α［J］. Cancer Invest, 2011, 29(6):377-382. ［17］ Mao Y, Xu J, Li Z, et al. The Role of Nuclear β-Catenin Accumulation in the Twist2Induced Ovarian Cancer EMT［J］. PLoS One, 2013, 8(11):e78200. ［18］ Kamino M, Kishida M, Kibe T, et al. Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2［J］. Cancer Sci, 2011, 102(3):540548. ［19］ Kessenbrock K, Dijkgraaf GJ, Lawson DA, et al. A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway［J］. Cell Stem Cell, 2013, 13(3):300-313. ［20］ Dey N, Young B, Abramovitz M, et al. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner［J］. PLoS One, 2013, 8(10):e77425. ［21］ Prasad CP, Chaurasiya SK, Axelsson L, et al. WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of breast cancer cells［J］. Mol Oncol， 2013, 7(5):870-883. ［22］ Li Y, Ma J, Qian X, et al. Regulation of EMT by Notch Signaling Pathway in Tumor Progression［J］. Curr Cancer Drug Targets， 2013, 13(9):957-962. ［23］ Wang T, Xuan X, Pian L, et al. Notch-1-mediated esophageal carcinoma EC-9706 cell invasion and metastasis by inducing epithelial-mesenchymal transition through Snail［J］. Tumour Biol， 2013, In press. ［24］ Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells［J］. Cancer Lett， 2011, 307(1):26-36. ［25］ Makinodan E, Marneros AG. Protein kinase A activation inhibits oncogenic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin［J］. Exp Dermatol， 2012, 21(11):847-852. ［26］ Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449［J］. N Engl J Med， 2009, 361(12):1173-1178. ［27］ Choe C, Shin YS, Kim SH, et al. Tumor-stromal interactions with direct cell contacts enhance motility of non-small cell lung cancer cells through the hedgehog signaling pathway［J］. Anticancer Res， 2013, 33(9):3715-3723. ［28］ Isohata N, Aoyagi K, Mabuchi T, et al. Hedgehog and epithelial-mesenchymal transition signaling in normal and malignant epithelial cells of the esophagus［J］. Int J Cancer, 2009, 125(5):1212-1221. ［29］ Chen JH, Wu H, Ma JP, et al. Effects of inhibition of Hedgehog signaling pathway for transforming growth factor-β-induced epithelial-mesenchymal transition［J］. Zhonghua Yi Xue Za Zhi, 2013, 93(26):2075-2078. ［30］ Lei J, Ma J, Ma Q, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligandindependent manner［J］. Mol Cancer, 2013, 12:66. ［31］ Ten Haaf A, Bektas N, Von Serenyi S, et al. Expression of the gliomaassociated oncogene homolog(GLI) 1 in human breast cancer is associated with unfavourable overall survival［J］. BMC Cancer, 2009, 9:2-12. ［32］ Liao X, Siu MK, Au CW, et al. Aberrant activation of hedgehog signaling pathway in ovarian cancers:effect on prognosis,cell invasion and differentiation［J］. Carcinogenesis, 2009, 30(1):131-140. ［33］ Keysar SB, Le PN, Anderson RT, et al. Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer［J］. Cancer Res， 2013, 73(11):3381-3392. ［34］ Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer［J］. Science, 2009, 324(5933):1457-1461. ［35］ Inaguma S, Kasai K, Ikeda H. GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin［J］. Oncogene, 2011, 30(6):714-723. ［36］ Hong KO, Kim JH, Hong JS, et al. Inhibition of Akt activity induces the mesenchymaltoepithelial reverting transition with restoring E-cadherin expression in KB and KOSCC25B oral squamous cell carcinoma cells［J］. J Exp Clin Cancer Res, 2009, 28:28. ［37］ 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. ［38］ Lin CY, Tsai PH, Kandaswami CC, et al. Role of tissue transglutaminase 2 in the acquisition of a mesenchymal-like phenotype in highly invasive A431 tumor cells［J］. Mol Cancer, 2011, 10:87. ［39］ Srivastava R K, Kurzrock R, Shankar S. MS-275 sensitizes TRAILresistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo［J］. Mol Cancer Ther, 2010, 9(12):3254-3266. ［40］ Yeasmin S, Nakayama K, Rahman MT, et al. Loss of MKK4 expression in ovarian cancer:a potential role for the epithelial to mesenchymal transition［J］. Int J Cancer, 2011, 128(1):94104. ［41］ Shao M, Cao L, Shen C, et al. Epithelial-to-mesenchymal transition and ovarian tumor progression induced by tissue transglutaminase［J］. Cancer Res, 2009, 69(24):9192-9201. ［42］ Chua HL, BhatNakshatri P, Clare SE, et al. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells:potential involvement of ZEB-1and ZEB-2［J］. Oncogene, 2007, 26(5):711-724. ［43］ Guo G, Yao W, Zhang Q, et al. Oleanolic acid suppresses migration and invasion of malignant glioma cells by inactivating MAPK/ERK signaling pathway［J］. PLoS One， 2013, 8(8):e72079. ［44］唐勇, 王辉, 陈伟娟, 等. EMT经p38-MAPK调节乳腺癌MCF-7细胞P-gp介导的多药耐药［J］. 中国肿瘤生物治疗杂志, 2010, 17(2):144-148. ［45］ Zhou X, Zhang Y, Han N, et al. α-Enolase (ENO1) inhibits epithelial-mesenchymal transition in the A549 cell line by suppressing ERK1/2 phosphorylation［J］. Zhongguo Fei Ai Za Zhi， 2013, 16(5):221-226.

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