Asian Pacific Journal of Cancer Prevention

  • 제15권9호
  • /
  • Pages.4013-4018
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  • 2014
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  • 1513-7368(pISSN)
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  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
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Low Expression of the FoxO4 Gene may Contribute to the Phenomenon of EMT in Non-small Cell Lung Cancer

  • Xu, Ming-Ming (Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University) ;
  • Mao, Guo-Xin (Department of Oncology, Affiliated Hospital of Nantong University) ;
  • Liu, Jian (Department of Oncology, Affiliated Hospital of Nantong University) ;
  • Li, Jian-Chao (Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University) ;
  • Huang, Hua (Department of Pathology, Affiliated Hospital of Nantong University) ;
  • Liu, Yi-Fei (Department of Pathology, Affiliated Hospital of Nantong University) ;
  • Liu, Jun-Hua (Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University)
  • 발행 : 2014.05.15
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초록

Because of its importance in tumor invasion and metastasis, the epithelial-mesenchymal transition (EMT) has become a research focus in the field of cancer. Recently, evidence has been presented that FoxO4 might be involved in EMT. Our study aimed to detect the expression of FoxO4, E-cadherin and vimentin in non-small cell lung cancers (NSCLCs). We also investigated clinical features and their correlations with the markers. In our study, FoxO4, E-cadherin and vimentin were assessed by immunohistochemistry in a tissue microarray (TMA) containing 150 cases of NSCLC. In addition, the expression level of FoxO4 protein was determined by Western blotting. The percentages of FoxO4, E-cadherin and vimentin positive expression in NSCLCs were 42.7%, 38.7% and 55.3%, respectively. Immunoreactivity of FoxO4 was low in NSCLC when compared with paired normal lung tissues. There were significant correlations between FoxO4 and TNM stage (P<0.001), histological differentiation (P=0.004) and lymph node metastasis (P<0.001), but no significant links with age (P=0.323), gender (P=0.410), tumor size (P=0.084), smoking status (P=0.721) and histological type (P=0.281). Our study showed that low expression of FoxO4 correlated with decreased expression of E-cadherin and elevated expression of vimentin. Cox regression analysis indicated FoxO4 to be an independent prognostic factor in NSCLC (P=0.046). These data suggested that FoxO4 might inhibit the process of EMT in NSCLC, and might therefore be a target for therapy.

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참고문헌

  1. Awaya H, Takeshima Y, Amatya VJ, et al (2005). Loss of expression of E-cadherin and beta-catenin is associated with progression of pulmonary adenocarcinoma. Pathol Int, 55, 14-8. https://doi.org/10.1111/j.1440-1827.2005.01784.x
  2. Berx G, Van Roy F (2001). The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res, 3, 289-93. https://doi.org/10.1186/bcr309
  3. Boura E, Silhan J, Herman P, et al (2007). Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding. J Biol Chem, 282, 8265-75. https://doi.org/10.1074/jbc.M605682200
  4. Bremnes RM, Veve R, Hirsch FR, Franklin WA (2002). The E-cadherin cell.cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer, 36, 115-24. https://doi.org/10.1016/S0169-5002(01)00471-8
  5. Burgering BM (2008). A brief introduction to FOXOlogy. Oncogene, 27, 2258-62. https://doi.org/10.1038/onc.2008.29
  6. Calnan DR, Brunet A (2008). The FoxO code. Oncogene, 27, 2276-88. https://doi.org/10.1038/onc.2008.21
  7. Chen L, Tang Y, Wang J, Yan Z, Xu R (2013). miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4. Biochem Biophys Res Commun, 435, 745-50. https://doi.org/10.1016/j.bbrc.2013.05.056
  8. Chuang PY, Yu Q, Fang W, Uribarri J, He JC (2007). Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor. Kidney Int, 72, 965-76. https://doi.org/10.1038/sj.ki.5002456
  9. Dansen TB, Smits LM, van Triest MH, et al (2009). Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nature Chem Biol, 5, 664-72. https://doi.org/10.1038/nchembio.194
  10. Fan FT, Shen CS, Tao L, et al (2014). PKM2 Regulates hepatocellular carcinoma cell epithelial-mesenchymal transition and migration upon EGFR activation. Asian Pac J Cancer Prev, 15, 1961-70. https://doi.org/10.7314/APJCP.2014.15.5.1961
  11. Foroni C, Broggini M, Generali D, Damia G (2012). Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. Cancer Treat Rev, 38, 689-97. https://doi.org/10.1016/j.ctrv.2011.11.001
  12. Geiger TR, Peeper DS (2009). Metastasis mechanisms. Biochim Biophys Acta-Reviews on Cancer, 1796, 293-308. https://doi.org/10.1016/j.bbcan.2009.07.006
  13. Groome PA, Bolejack V, Crowley JJ, et al (2007). The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol, 2, 694-705. https://doi.org/10.1097/JTO.0b013e31812d05d5
  14. Ivaska J (2011). Vimentin: Central hub in EMT induction? Small Gtpases, 2, 51-3. https://doi.org/10.4161/sgtp.2.1.15114
  15. Jemal A, Siegel R, Ward E, et al (2008). Cancer statistics, 2008. CA Cancer J Clin, 58, 71-96. https://doi.org/10.3322/CA.2007.0010
  16. Joo YE, Rew JS, Choi SK, et al (2002). Expression of E-cadherin and catenins in early gastric cancer. J Clin Gastroenterol, 35, 35-42. https://doi.org/10.1097/00004836-200207000-00009
  17. Joo YE, Rew JS, Park CS, Kim SJ (2002). Expression of E-cadherin, alpha-and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology, 2, 129-37. https://doi.org/10.1159/000055903
  18. Kalluri R, Weinberg RA (2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119, 1420. https://doi.org/10.1172/JCI39104
  19. Katoh M (2004). Human FOX gene family (Review). Int J Oncol, 25, 1495-500.
  20. Kops GJ, de Ruiter ND, De Vries-Smits AM, et al (1999). Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature, 398, 630-4. https://doi.org/10.1038/19328
  21. Lee MJ, Yu GR, Yoo HJ, et al (2009). ANXA8 down-regulation by EGF-FOXO4 signaling is involved in cell scattering and tumor metastasis of cholangiocarcinoma. Gastroenterology, 137, 1138-50, 50 e1-9. https://doi.org/10.1053/j.gastro.2009.04.015
  22. Liu X, Zhang Z, Sun L, et al (2011). MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis, 32, 1798-805. https://doi.org/10.1093/carcin/bgr213
  23. Liu Y (2010). New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol, 21, 212-22. https://doi.org/10.1681/ASN.2008121226
  24. Lopez-Novoa JM, Nieto MA (2009). Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med, 1, 303-14. https://doi.org/10.1002/emmm.200900043
  25. Lupertz R, Chovolou Y, Unfried K, et al (2008). The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis, 29, 2045-52. https://doi.org/10.1093/carcin/bgn184
  26. McGary EC, Lev DC, Bar-Eli M (2002). Cellular adhesion pathways and metastatic potential of human melanoma. Cancer Biol Ther, 1, 459-65. https://doi.org/10.4161/cbt.1.5.158
  27. Obsilova V, Vecer J, Herman P, et al (2005). 14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4. Biochemistry, 44, 11608-17. https://doi.org/10.1021/bi050618r
  28. Satelli A, Li S (2011). Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci, 68, 3033-46. https://doi.org/10.1007/s00018-011-0735-1
  29. Shi X, Wallis AM, Gerard RD, et al (2012). Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2. J Cell Sci, 125, 5329-37. https://doi.org/10.1242/jcs.105239
  30. Silhan J, Vacha P, Strnadova P, et al (2009). 14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4. J Biol Chem, 284, 19349-60. https://doi.org/10.1074/jbc.M109.002725
  31. Soltermann A, Tischler V, Arbogast S, et al (2008). Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non.small cell lung cancer. Clin Cancer Res, 14, 7430-7. https://doi.org/10.1158/1078-0432.CCR-08-0935
  32. Su CY, Li YS, Han Y, Zhou SJ, Liu ZD (2014). Correlation between expression of cell adhesion molecules CD44 v6 and E-cadherin and lymphatic metastasis in non- small cell lung cancer. Asian Pac J Cancer Prev, 15, 2221-4. https://doi.org/10.7314/APJCP.2014.15.5.2221
  33. Tang TT, Lasky LA (2003). The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. J Biol Chem, 278, 30125-35. https://doi.org/10.1074/jbc.M302042200
  34. Thiery JP, Acloque H, Huang RY, Nieto MA (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139, 871-90. https://doi.org/10.1016/j.cell.2009.11.007
  35. Tran H, Brunet A, Grenier JM, et al (2002). DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science, 296, 530-4. https://doi.org/10.1126/science.1068712
  36. Tsao S, Liu Y, Wang X, et al (2003). The association of E-cadherin expression and the methylation status of the E-cadherin gene in nasopharyngeal carcinoma cells. Eur J Cancer, 39, 524-31. https://doi.org/10.1016/S0959-8049(02)00494-X
  37. Vaid M, Singh T, Katiyar SK (2011). Grape seed proanthocyanidins inhibit melanoma cell invasiveness by reduction of PGE2 synthesis and reversal of epithelial-to-mesenchymal transition. PLoS One, 6, e21539. https://doi.org/10.1371/journal.pone.0021539
  38. Wang G, Dong W, Shen H, et al (2011). A comparison of Twist and E-cadherin protein expression in primary non-small-cell lung carcinoma and corresponding metastases. European J Cardio-Thoracic Surg 39, 1028-32. https://doi.org/10.1016/j.ejcts.2011.01.023
  39. Wells A, Yates C, Shepard CR (2008). E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis, 25, 621-8. https://doi.org/10.1007/s10585-008-9167-1
  40. Wen C, Dehnel T (2011). China wrestles with lung cancer. Lancet Oncol, 12, 15. https://doi.org/10.1016/S1470-2045(10)70303-X
  41. Xiang-qiang L, Shan-hong T, Zhi-yong Z, Hai-feng J (2011). [Expression and clinical significance of FOX04 in colorectal cancer]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 27, 969-71.
  42. Xu B, Jin DY, Lou WH, Wang DS (2013). Lipocalin-2 is associated with a good prognosis and reversing epithelial-to-mesenchymal transition in pancreatic cancer. World J Surg, 37, 1892-900. https://doi.org/10.1007/s00268-013-2009-6
  43. Yang H, Zhao R, Yang HY, Lee MH (2005). Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene, 24, 1924-35. https://doi.org/10.1038/sj.onc.1208352
  44. Zhao ZY, Han CG, Liu JT, et al (2013). TIAM2 enhances non-small cell lung cancer cell invasion and motility. Asian Pac J Cancer Prev, 14, 6305-9. https://doi.org/10.7314/APJCP.2013.14.11.6305

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