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Inflammation and Lung Cancer: The Role of Epithelial–Mesenchymal Transition

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Inflammation and Lung Cancer

Abstract

Epithelial–mesenchymal transition (EMT) is a type of cellular plasticity by which epithelial cells acquire the form and function of mesenchymal cells. Physiologic EMT is an essential part of normal embryonic development and an adult organism’s ability to overcome acute injury. However, chronic injury and inflammation can yield dysregulated or pathologic EMT that drives organ fibrosis and cancer development. In this chapter, we review seminal work and recent findings regarding the molecular, cellular, microenvironmental, and environmental factors that drive inflammation-induced EMT-dependent lung carcinogenesis. We also discuss potential approaches for treating or perhaps preventing lung cancer by targeting the inflammation-EMT-cancer axis.

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References

  1. Barbieri SS, Weksler BB (2007) Tobacco smoke cooperates with interleukin-1beta to alter beta-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo. FASEB J 21(8):1831–1843

    CAS  PubMed  Google Scholar 

  2. Rom O, Avezov K, Aizenbud D, Reznick AZ (2013) Cigarette smoking and inflammation revisited. Respir Physiol Neurobiol 187(1):5–10

    CAS  PubMed  Google Scholar 

  3. Walser T, Cui X, Yanagawa J, Lee JM, Heinrich E, Lee G, et al. (2008) Smoking and lung cancer: the role of inflammation. Proc Am Thorac Soc 5(8):811–815

    PubMed Central  PubMed  Google Scholar 

  4. Heinrich EL, Walser TC, Krysan K, Liclican EL, Grant JL, Rodriguez NL, Dubinett SM (2012) The inflammatory tumor microenvironment, epithelial mesenchymal transition and lung carcinogenesis. Cancer Microenviron 5(1):5–18

    CAS  PubMed Central  PubMed  Google Scholar 

  5. O’Callaghan DS, O’Donnell D, O’Connell F, O’Byrne KJ (2010) The role of inflammation in the pathogenesis of non-small cell lung cancer. J Thorac Oncol 5(12):2024–2036

    PubMed  Google Scholar 

  6. Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22(1):33–40

    CAS  PubMed  Google Scholar 

  7. Gomes M, Teixeira AL, Coelho A, Araujo A, Medeiros R (2014) The role of inflammation in lung cancer. Adv Exp Med Biol 816:1–23

    CAS  PubMed  Google Scholar 

  8. Franks AL, Slansky JE (2012) Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 32(4):1119–1136

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    CAS  PubMed  Google Scholar 

  10. Pasche B, Wang M, Pennison M, Jimenez H (2014) Prevention and treatment of cancer with aspirin: where do we stand? Semin Oncol 41(3):397–401

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW (2011) Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377(9759):31–41

    CAS  PubMed  Google Scholar 

  12. Thorat MA, Cuzick J (2013) Role of aspirin in cancer prevention. Curr Oncol Rep 15(6):533–540

    CAS  PubMed  Google Scholar 

  13. Thun MJ, Jacobs EJ, Patrono C (2012) The role of aspirin in cancer prevention. Nat Rev Clin Oncol 9(5):259–267

    CAS  PubMed  Google Scholar 

  14. Bauer AK, Rondini EA (2009) Review paper: the role of inflammation in mouse pulmonary neoplasia. Vet Pathol 46(3):369–390

    CAS  PubMed  Google Scholar 

  15. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6(1):24–37

    PubMed  Google Scholar 

  16. Schafer M, Werner S (2008) Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9(8):628–638

    CAS  PubMed  Google Scholar 

  17. Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15(6):740–746

    CAS  PubMed  Google Scholar 

  18. Lee K, Nelson CM (2012) New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol 294:171–221

    CAS  PubMed  Google Scholar 

  19. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME (1996) Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67(2):275–282

    CAS  PubMed  Google Scholar 

  21. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A (2012) Go or grow: the key to the emergence of invasion in tumour progression? Math Med Biol 29(1):49–65

    CAS  PubMed  Google Scholar 

  22. Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119(6):1429–1437

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Massague J (2008) TGFbeta in Cancer. Cell 134(2):215–230

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Samet JM (2000) Does idiopathic pulmonary fibrosis increase lung cancer risk? Am J Respir Crit Care Med 161(1):1–2

    CAS  PubMed  Google Scholar 

  25. Willis BC, Borok Z (2007) TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol 293(3):L525–534

    CAS  PubMed  Google Scholar 

  26. Roberts AB, Wakefield LM (2003) The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A 100(15):8621–8623

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ (2008) Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol 38(1):95–104

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol 174(2):175–183

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Aoyama D, Hashimoto N, Sakamoto K, Kohnoh T, Kusunose M, Kimura M, et al. (2013) Involvement of TGFbeta-induced phosphorylation of the PTEN C-terminus on TGFbeta-induced acquisition of malignant phenotypes in lung cancer cells. PLoS ONE 8(11):e81133

    PubMed Central  PubMed  Google Scholar 

  30. Ohshio Y, Teramoto K, Hashimoto M, Kitamura S, Hanaoka J, Kontani K (2013) Inhibition of transforming growth factor-beta release from tumor cells reduces their motility associated with epithelial-mesenchymal transition. Oncol Rep 30(2):1000–1006

    CAS  PubMed  Google Scholar 

  31. Abulaiti A, Shintani Y, Funaki S, Nakagiri T, Inoue M, Sawabata N, et al. (2013) Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-beta signaling by IL-6. Lung Cancer 82(2):204–213

    PubMed  Google Scholar 

  32. Grant JL, Fishbein MC, Hong LS, Krysan K, Minna JD, Shay JW, et al. (2014) A novel molecular pathway for snail-dependent, SPARC-mediated invasion in non-small cell lung cancer pathogenesis. Cancer Prev Res (Phila) 7(1):150–160

    CAS  Google Scholar 

  33. Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, et al. (2011) Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 9(9):e1001162

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Izumchenko E, Chang X, Michailidi C, Kagohara L, Ravi R, Paz K, et al. (2014) The TGFbeta-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res 74(14):3995–4005

    CAS  PubMed  Google Scholar 

  35. Kitamura K, Seike M, Okano T, Matsuda K, Miyanaga A, Mizutani H, et al. (2014) MiR-134/487b/655 cluster regulates TGF-beta-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells. Mol Cancer Ther 13(2):444–453

    CAS  PubMed  Google Scholar 

  36. Zarogoulidis P, Yarmus L, Darwiche K, Walter R, Huang H, Li Z, et al. (2013) Interleukin-6 cytokine: a multifunctional glycoprotein for cancer. Immunome Res 9(62):16535

    PubMed Central  PubMed  Google Scholar 

  37. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P (2011) IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 9(12):1658–1667

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 70(17):6945–6956

    CAS  PubMed  Google Scholar 

  39. Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, et al. (2012) Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS ONE 7(12):e50165

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Bao B, Ahmad A, Kong D, Ali S, Azmi AS, Li Y, et al. (2012) Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS ONE 7(8):e43726

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Dalwadi H, Krysan K, Heuze-Vourc’h N, Dohadwala M, Elashoff D, Sharma S, et al. (2005) Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clin Cancer Res 11(21):7674–7682

    CAS  PubMed  Google Scholar 

  42. Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T, et al. (2010) TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A 107(35):15535–15540

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, et al. (2012) Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2 + breast cancer by expanding the cancer stem cell population. Mol Cell 47(4):570–584

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Giles KM, Kalinowski FC, Candy PA, Epis MR, Zhang PM, Redfern AD, et al. (2013) Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther 12(11):2541–2558

    CAS  PubMed  Google Scholar 

  45. Carstens JL, Lovisa S, Kalluri R (2014) Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch. J Clin Invest 124(4):1458–1460

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. (2014) IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 124(4):1853–1867

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745–756

    CAS  PubMed  Google Scholar 

  48. Kim V, Rogers TJ, Criner GJ (2008) New concepts in the pathobiology of chronic obstructive pulmonary disease. Proc Am Thorac Soc 5(4):478–485

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Mukhopadhyay S, Hoidal JR, Mukherjee TK (2006) Role of TNFalpha in pulmonary pathophysiology. Respir Res 7:125

    PubMed Central  PubMed  Google Scholar 

  50. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15(5):416–428

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Kawata M, Koinuma D, Ogami T, Umezawa K, Iwata C, Watabe T, Miyazono K (2012) TGF-beta-induced epithelial-mesenchymal transition of A549 lung adenocarcinoma cells is enhanced by pro-inflammatory cytokines derived from RAW 264.7 macrophage cells. J Biochem 151(2):205–216

    CAS  PubMed  Google Scholar 

  52. Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, et al. (2012) Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res 72(5):1290–1300

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Shiozaki A, Bai XH, Shen-Tu G, Moodley S, Takeshita H, Fung SY, et al. (2012) Claudin 1 mediates TNFalpha-induced gene expression and cell migration in human lung carcinoma cells. PLoS ONE 7(5):e38049

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Saito A, Suzuki HI, Horie M, Ohshima M, Morishita Y, Abiko Y, Nagase T (2013) An integrated expression profiling reveals target genes of TGF-beta and TNF-alpha possibly mediated by microRNAs in lung cancer cells. PLoS ONE 8(2):e56587

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Apte RN, Voronov E (2002) Interleukin-1–a major pleiotropic cytokine in tumor-host interactions. Semin Cancer Biol 12(4):277–290

    CAS  PubMed  Google Scholar 

  56. Colasante A, Mascetra N, Brunetti M, Lattanzio G, Diodoro M, Caltagirone S, et al. (1997) Transforming growth factor beta 1, interleukin-8 and interleukin-1, in non-small-cell lung tumors. Am J Respir Crit Care Med 156(3 Pt 1):968–973

    CAS  PubMed  Google Scholar 

  57. Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, et al. (2006) Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions. Eur J Cancer 42(6):751–759

    CAS  PubMed  Google Scholar 

  58. Giavazzi R, Garofalo A, Bani MR, Abbate M, Ghezzi P, Boraschi D, et al. (1990) Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res 50(15):4771–4775

    CAS  PubMed  Google Scholar 

  59. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. (2008) Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14(5):408–419

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Krelin Y, Voronov E, Dotan S, Elkabets M, Reich E, Fogel M, et al. (2007) Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res 67(3):1062–1071

    CAS  PubMed  Google Scholar 

  61. Yano S, Nokihara H, Yamamoto A, Goto H, Ogawa H, Kanematsu T, et al. (2003) Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules. Cancer Sci 94(3):244–252

    CAS  PubMed  Google Scholar 

  62. Heinrich EL, Charuworn B, Dohadwala M, Dubinett SM (2008) IL-1B dependent epithelial-mesenchymal transition in non-small cell lung cancer [abstract]. In: Proceedings of the Frontiers in Cancer Prevention Research Conference - November 16-18, Washington, DC : Cancer Prev Res 1(7 Suppl): Abstract 26

    Google Scholar 

  63. St John MA, Dohadwala M, Luo J, Wang G, Lee G, Shih H, et al. (2009) Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma. Clin Cancer Res 15(19):6018–6027

    Google Scholar 

  64. Dong GW, Do NY, Lim SC (2010) Relation between proinflammatory mediators and epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Exp Ther Med 1(5):885–891

    PubMed Central  PubMed  Google Scholar 

  65. Dohadwala M, Wang G, Heinrich E, Luo J, Lau O, Shih H, et al. (2010) The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. Otolaryngol Head Neck Surg 142(5):753–759

    PubMed  Google Scholar 

  66. Kiefel H, Bondong S, Pfeifer M, Schirmer U, Erbe-Hoffmann N, Schafer H, et al. (2012) EMT-associated up-regulation of L1CAM provides insights into L1CAM-mediated integrin signalling and NF-kappaB activation. Carcinogenesis 33(10):1919–1929

    CAS  PubMed  Google Scholar 

  67. Lee CH, Chang JS, Syu SH, Wong TS, Chan JY, Tang YC, et al. (2015) IL-1B promotes malignant transformation and tumor aggressiveness in oral cancer. J Cell Physiol 230(4): 875–884

    Google Scholar 

  68. Leibovich-Rivkin T, Liubomirski Y, Bernstein B, Meshel T, Ben-Baruch A (2013) Inflammatory factors of the tumor microenvironment induce plasticity in nontransformed breast epithelial cells: EMT, invasion, and collapse of normally organized breast textures. Neoplasia 15(12):1330–1346

    PubMed Central  PubMed  Google Scholar 

  69. Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J (2012) IL-1beta promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer 11:87

    PubMed Central  PubMed  Google Scholar 

  70. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925

    CAS  PubMed  Google Scholar 

  71. Trusolino L, Bertotti A, Comoglio PM MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11(12):834–848

    Google Scholar 

  72. Birchmeier C, Gherardi E (1998) Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8(10):404–410

    CAS  PubMed  Google Scholar 

  73. Siegfried JM, Weissfeld LA, Luketich JD, Weyant RJ, Gubish CT, Landreneau RJ (1998) The clinical significance of hepatocyte growth factor for non-small cell lung cancer. Ann Thorac Surg 66(6):1915–1918

    CAS  PubMed  Google Scholar 

  74. Siegfried JM, Luketich JD, Stabile LP, Christie N, Land SR (2004) Elevated hepatocyte growth factor level correlates with poor outcome in early-stage and late-stage adenocarcinoma of the lung. Chest 125(5 Suppl):116S–119S

    CAS  PubMed  Google Scholar 

  75. Grotegut S, von Schweinitz D, Christofori G, Lehembre F (2006) Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of snail. EMBO J 25(15):3534–3545

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M (2001) Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 20(56):8125–8135

    CAS  PubMed  Google Scholar 

  77. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, et al. (2003) Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22(13):2021–2033

    CAS  PubMed  Google Scholar 

  78. Canadas I, Rojo F, Taus A, Arpi O, Arumi-Uria M, Pijuan L, et al. (2014) Targeting epithelial-to-mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer. Clin Cancer Res 20(4):938–950

    CAS  PubMed  Google Scholar 

  79. Yu G, Jing Y, Kou X, Ye F, Gao L, Fan Q, et al. (2013) Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma. PLoS ONE 8(9):e73312

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Ogunwobi OO, Puszyk W, Dong HJ, Liu C (2013) Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma. PLoS ONE 8(5):e63765

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE (1998) Cyclooxygenase in biology and disease. FASEB J 12(12):1063–1073

    CAS  PubMed  Google Scholar 

  82. Lee JM, Yanagawa J, Peebles KA, Sharma S, Mao JT, Dubinett SM (2008) Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment. Crit Rev Oncol Hematol 66(3):208–217

    PubMed Central  PubMed  Google Scholar 

  83. Krysan K, Reckamp KL, Dalwadi H, Sharma S, Rozengurt E, Dohadwala M, Dubinett SM (2005) Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res 65(14):6275–6281

    CAS  PubMed  Google Scholar 

  84. Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, et al. (1998) Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 58(17):3761–3764

    CAS  PubMed  Google Scholar 

  85. Krysan K, Dalwadi H, Sharma S, Pold M, Dubinett S (2004) Cyclooxygenase 2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer. Cancer Res 64(18):6359–6362

    CAS  PubMed  Google Scholar 

  86. Baratelli F, Lin Y, Zhu L, Yang SC, Heuze-Vourc’h N, Zeng G, et al. (2005) Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4 + T cells. J Immunol 175(3):1483–1490

    CAS  PubMed  Google Scholar 

  87. Dohadwala M, Batra RK, Luo J, Lin Y, Krysan K, Pold M, et al. (2002) Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion. J Biol Chem 277(52):50828–50833

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M, et al. (2006) Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res 66(10):5338–5345

    CAS  PubMed  Google Scholar 

  89. Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA (2012) FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCgamma/COX-2-mediated mechanisms. PLoS ONE 7(6):e38972

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Kirane A, Toombs JE, Ostapoff K, Carbon JG, Zaknoen S, Braunfeld J, et al. (2012) Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. Clin Cancer Res 18(18):5031–5042

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Adhim Z, Matsuoka T, Bito T, Shigemura K, Lee KM, Kawabata M, et al. (2011) In vitro and in vivo inhibitory effect of three Cox-2 inhibitors and epithelial-to-mesenchymal transition in human bladder cancer cell lines. Br J Cancer 105(3):393–402

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Fujii R, Imanishi Y, Shibata K, Sakai N, Sakamoto K, Shigetomi S, et al. (2014) Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. J Exp Clin Cancer Res 33:40

    PubMed Central  PubMed  Google Scholar 

  93. St John MA, Wang G, Luo J, Dohadwala M, Hu D, Lin Y, et al. (2012) Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies. Br J Cancer 107(4):707–712

    Google Scholar 

  94. Peebles KA, Lee JM, Mao JT, Hazra S, Reckamp KL, Krysan K, et al. (2007) Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther 7(10):1405–1421

    CAS  PubMed  Google Scholar 

  95. Chapman HA (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73:413–435

    CAS  PubMed  Google Scholar 

  96. Zheng H, Shen M, Zha YL, Li W, Wei Y, Blanco MA, et al. (2014) PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell 26(3):358–373

    CAS  PubMed  Google Scholar 

  97. Fuchs SY, Chen A, Xiong Y, Pan ZQ, Ronai Z (1999) HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Oncogene 18(12):2039–2046

    CAS  PubMed  Google Scholar 

  98. Kumar M, Allison DF, Baranova NN, Wamsley JJ, Katz AJ, Bekiranov S, et al. (2013) NF-kappaB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells. PLoS ONE 8(7):e68597

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Sun Q, Yao X, Ning Y, Zhang W, Zhou G, Dong Y (2013) Overexpression of response gene to complement 32 (RGC32) promotes cell invasion and induces epithelial-mesenchymal transition in lung cancer cells via the NF-kappaB signaling pathway. Tumour Biol 34(5):2995–3002

    CAS  PubMed  Google Scholar 

  100. Zhao Y, Xu Y, Li Y, Xu W, Luo F, Wang B, et al. (2013) NF-kappaB-mediated inflammation leading to EMT via miR-200c is involved in cell transformation induced by cigarette smoke extract. Toxicol Sci 135(2):265–276

    CAS  PubMed  Google Scholar 

  101. Sheshadri N, Catanzaro JM, Bott AJ, Sun Y, Ullman E, Chen EI, et al. (2014) SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling. Cancer Res 74(21): 6318–6329.

    Google Scholar 

  102. Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M (2009) Role of Ras signaling in the induction of snail by transforming growth factor-beta. J Biol Chem 284(1):245–253

    CAS  PubMed  Google Scholar 

  103. Dhasarathy A, Phadke D, Mav D, Shah RR, Wade PA (2011) The transcription factors Snail and Slug activate the transforming growth factor-beta signaling pathway in breast cancer. PLoS ONE 6(10):e26514

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Zheng P, Meng HM, Gao WZ, Chen L, Liu XH, Xiao ZQ, et al. (2011) Snail as a key regulator of PRL-3 gene in colorectal cancer. Cancer Biol Ther 12(8):742–749

    CAS  PubMed  Google Scholar 

  105. Peinado H, Ballestar E, Esteller M, Cano A (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell. Biol. 24(1):306–319

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Peinado H, Quintanilla M, Cano A (2003) Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278(23):21113–21123

    CAS  PubMed  Google Scholar 

  107. Yanagawa J, Walser TC, Zhu LX, Hong L, Fishbein MC, Mah V, et al. (2009) Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma. Clin Cancer Res 15(22):6820–6829

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Yang Y, Li Y, Wang K, Wang Y, Yin W, Li L (2013) P38/NF-kappaB/snail pathway is involved in caffeic acid-induced inhibition of cancer stem cells-like properties and migratory capacity in malignant human keratinocyte. PLoS ONE 8(3):e58915

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Ishii G, Hashimoto H, Atsumi N, Hoshino A, Ochiai A (2013) Morphophenotype of floating colonies derived from a single cancer cell has a critical impact on tumor-forming activity. Pathol Int 63(1):29–36

    CAS  PubMed  Google Scholar 

  110. Sanchez-Garcia I (2009) The crossroads of oncogenesis and metastasis. New England Journal of Medicine 360(3):297–299

    CAS  PubMed  Google Scholar 

  111. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Walser TC, Yanagawa J, Garon E, Lee JM, Dubinett SM (2010) Tumor microenvironment. In: Stewart DJ (ed) Lung cancer: prevention, management and emerging therapies, current clinical oncology. Humana Press, New York, pp 27–69

    Google Scholar 

  113. Du F, Nakamura Y, Tan TL, Lee P, Lee R, Yu B, Jamora C (2010) Expression of snail in epidermal keratinocytes promotes cutaneous inflammation and hyperplasia conducive to tumor formation. Cancer Res 70(24):10080–10089

    CAS  PubMed  Google Scholar 

  114. Hahn S, Jackstadt R, Siemens H, Hunten S, Hermeking H (2013) SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. EMBO J 32(23):3079–3095

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Kim E, Youn H, Kwon T, Son B, Kang J, Yang HJ, et al. (2014) PAK1 Tyrosine phosphorylation is required to induce epithelial-mesenchymal transition and radioresistance in lung cancer cells. Cancer Res 74(19):5520–5531

    CAS  PubMed  Google Scholar 

  116. Krohn A, Ahrens T, Yalcin A, Plones T, Wehrle J, Taromi S, et al. (2014) Tumor cell heterogeneity in Small Cell Lung Cancer (SCLC): phenotypical and functional differences associated with Epithelial-Mesenchymal Transition (EMT) and DNA methylation changes. PLoS ONE 9(6):e100249

    PubMed Central  PubMed  Google Scholar 

  117. Millanes-Romero A, Herranz N, Perrera V, Iturbide A, Loubat-Casanovas J, Gil J, et al. (2013) Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition. Mol Cell 52(5):746–757

    CAS  PubMed  Google Scholar 

  118. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, et al. (2013) MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154(2):311–324

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Shah PP, Lockwood WW, Saurabh K, Kurlawala Z, Shannon SP, Waigel S, et al. (2015) Ubiquilin1 represses migration and epithelial-to-mesenchymal transition of human non-small cell lung cancer cells. Oncogene 34(13): 1709–1717

    Google Scholar 

  120. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29(5):625–634

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47

    CAS  PubMed  Google Scholar 

  122. Nizet V, Johnson RS (2009) Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9(9):609–617

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Fitzpatrick SF, Tambuwala MM, Bruning U, Schaible B, Scholz CC, Byrne A, et al. (2011) An intact canonical NF-kappaB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol 186(2):1091–1096

    CAS  PubMed  Google Scholar 

  124. Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. (2009) HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest 119(8):2160–2170

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117(12):3810–3820

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, et al. (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66(7):3567–3575

    CAS  PubMed  Google Scholar 

  127. Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, Semenza GL (2006) Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66(5):2725–2731

    CAS  PubMed  Google Scholar 

  128. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, et al. (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305

    CAS  PubMed  Google Scholar 

  129. Gort EH, van Haaften G, Verlaan I, Groot AJ, Plasterk RH, Shvarts A, et al. (2008) The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha. Oncogene 27(11):1501–1510

    CAS  PubMed  Google Scholar 

  130. Hung JJ, Yang MH, Hsu HS, Hsu WH, Liu JS, Wu KJ (2009) Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax 64(12):1082–1089

    PubMed  Google Scholar 

  131. Luo D, Wang J, Li J, Post M (2011) Mouse snail is a target gene for HIF. Mol Cancer Res 9(2):234–245

    CAS  PubMed  Google Scholar 

  132. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A 105(17):6392–6397

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Chen J, Imanaka N, Griffin JD (2010) Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer 102(2):351–360

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361

    PubMed  Google Scholar 

  135. Jiang YG, Luo Y, He DL, Li X, Zhang LL, Peng T, et al. (2007) Role of Wnt/beta-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha. Int J Urol 14(11):1034–1039

    CAS  PubMed  Google Scholar 

  136. Zhou G, Dada LA, Wu M, Kelly A, Trejo H, Zhou Q, et al. (2009) Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol 297(6):L1120–1130

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Chen Y, Li D, Liu H, Xu H, Zheng H, Qian F, et al. (2011) Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells. Cancer Biol Ther 11(1):14–21

    CAS  PubMed  Google Scholar 

  138. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, et al. (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440(7088):1222–1226

    CAS  PubMed  Google Scholar 

  139. Huang CH, Yang WH, Chang SY, Tai SK, Tzeng CH, Kao JY, et al. (2009) Regulation of membrane-type 4 matrix metalloproteinase by SLUG contributes to hypoxia-mediated metastasis. Neoplasia 11(12):1371–1382

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Yoo YG, Christensen J, Huang LE (2011) HIF-1alpha confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function. Cancer Res 71(4):1244–1252

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Brookes PS, Levonen AL, Shiva S, Sarti P, Darley-Usmar VM (2002) Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species. Free Radic Biol Med 33(6):755–764

    CAS  PubMed  Google Scholar 

  142. Chatterjee S, Fisher AB (2004) ROS to the rescue. Am J Physiol Lung Cell Mol Physiol 287(4):L704–705

    CAS  PubMed  Google Scholar 

  143. Hancock JT, Desikan R, Neill SJ (2001) Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans 29(Pt 2):345–350

    CAS  PubMed  Google Scholar 

  144. Sauer H, Wartenberg M, Hescheler J (2001) Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 11(4):173–186

    CAS  PubMed  Google Scholar 

  145. Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279(6):L1005–1028

    CAS  PubMed  Google Scholar 

  146. Rosanna DP, Salvatore C (2012) Reactive oxygen species, inflammation, and lung diseases. Curr Pharm Des 18(26):3889–3900

    PubMed  Google Scholar 

  147. Mates JM, Segura JA, Alonso FJ, Marquez J (2008) Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. Arch Toxicol 82(5):273–299

    CAS  PubMed  Google Scholar 

  148. Paz-Elizur T, Sevilya Z, Leitner-Dagan Y, Elinger D, Roisman LC, Livneh Z (2008) DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett 266(1):60–72

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313(Pt 1):17–29

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Delaney S, Jarem DA, Volle CB, Yennie CJ (2012) Chemical and biological consequences of oxidatively damaged guanine in DNA. Free Radic Res 46(4):420–441

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Kawanishi S, Hiraku Y, Oikawa S (2001) Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. Mutat Res 488(1):65–76

    CAS  PubMed  Google Scholar 

  152. Jackson JH (1994) Potential molecular mechanisms of oxidant-induced carcinogenesis. Environ Health Perspect 102(Suppl 10):155–157

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Malins DC, Polissar NL, Gunselman SJ (1996) Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage. Proc Natl Acad Sci U S A 93(6):2557–2563

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, et al. (1993) p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 53(20):4817–4822

    CAS  PubMed  Google Scholar 

  155. Denissenko MF, Pao A, Tang M, Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274(5286):430–432

    CAS  PubMed  Google Scholar 

  156. Lauber K, Blumenthal SG, Waibel M, Wesselborg S (2004) Clearance of apoptotic cells: getting rid of the corpses. Mol Cell 14(3):277–287

    CAS  PubMed  Google Scholar 

  157. Maderna P, Godson C (2003) Phagocytosis of apoptotic cells and the resolution of inflammation. Biochim Biophys Acta 1639(3):141–151

    CAS  PubMed  Google Scholar 

  158. Crawford DR, Abramova NE, Davies KJ (1998) Oxidative stress causes a general, calcium-dependent degradation of mitochondrial polynucleotides. Free Radic Biol Med 25(9):1106–1111

    CAS  PubMed  Google Scholar 

  159. Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, et al. (1993) Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science 262(5137):1274–1277

    CAS  PubMed  Google Scholar 

  160. Kristal BS, Chen J, Yu BP (1994) Sensitivity of mitochondrial transcription to different free radical species. Free Radic Biol Med 16(3):323–329

    CAS  PubMed  Google Scholar 

  161. Reed JC (1997) Cytochrome c: can’t live with it–can’t live without it. Cell 91(5):559–562

    CAS  PubMed  Google Scholar 

  162. Benhar M, Dalyot I, Engelberg D, Levitzki A (2001) Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 21(20):6913–6926

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS (2004) Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem 279(33):34643–34654

    CAS  PubMed  Google Scholar 

  164. Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, et al. (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320(5876):661–664

    CAS  PubMed  Google Scholar 

  165. Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24(5):981–990

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58(5–6):262–270

    CAS  PubMed Central  PubMed  Google Scholar 

  167. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475(7354):106–109

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Ding M, Li JJ, Leonard SS, Ye JP, Shi X, Colburn NH, et al. (1999) Vanadate-induced activation of activator protein-1: role of reactive oxygen species. Carcinogenesis 20(4):663–668

    CAS  PubMed  Google Scholar 

  169. Ding M, Shi X, Lu Y, Huang C, Leonard S, Roberts J, et al. (2001) Induction of activator protein-1 through reactive oxygen species by crystalline silica in JB6 cells. J Biol Chem 276(12):9108–9114

    CAS  PubMed  Google Scholar 

  170. Suzuki T, Murakami M, Onai N, Fukuda E, Hashimoto Y, Sonobe MH, et al. (1994) Analysis of AP-1 function in cellular transformation pathways. J Virol 68(6):3527–3535

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Wilhelm D, Bender K, Knebel A, Angel P (1997) The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents. Mol Cell Biol 17(8):4792–4800

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Devalia JL, Davies RJ (1993) Airway epithelial cells and mediators of inflammation. Respir Med 87(6):405–408

    CAS  PubMed  Google Scholar 

  173. Rahman I, Gilmour PS, Jimenez LA, MacNee W (2002) Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem 234–235(1–2):239–248

    PubMed  Google Scholar 

  174. Akira S, Kishimoto T (1997) NF-IL6 and NF-kappa B in cytokine gene regulation. Adv Immunol 65:1–46

    CAS  PubMed  Google Scholar 

  175. Sethi G, Sung B, Aggarwal BB (2008) Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood) 233(1):21–31

    CAS  Google Scholar 

  176. Brennan FM, Maini RN, Feldmann M (1995) Cytokine expression in chronic inflammatory disease. Br Med Bull 51(2):368–384

    CAS  PubMed  Google Scholar 

  177. Ward PA (1996) Role of complement, chemokines, and regulatory cytokines in acute lung injury. Ann N Y Acad Sci 796:104–112

    CAS  PubMed  Google Scholar 

  178. Bartis D, Mise N, Mahida RY, Eickelberg O, Thickett DR (2014) Epithelial-mesenchymal transition in lung development and disease: does it exist and is it important? Thorax 69(8):760–765

    PubMed  Google Scholar 

  179. Bartis D, Thickett DR (2014) Authors’ response: epithelial-mesenchymal transition (EMT) is a common molecular programme in epithelial cells which can be triggered by injury. Thorax 69(8):769

    PubMed  Google Scholar 

  180. Young RP, Whittington CF, Hopkins RJ, Hay BA, Epton MJ, Black PN, Gamble GD (2010) Chromosome 4q31 locus in COPD is also associated with lung cancer. Eur Respir J 36(6):1375–1382

    CAS  PubMed  Google Scholar 

  181. Zou W, Zou Y, Zhao Z, Li B, Ran P (2013) Nicotine-induced epithelial-mesenchymal transition via Wnt/beta-catenin signaling in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 304(4):L199–209

    CAS  PubMed  Google Scholar 

  182. Nagathihalli NS, Massion PP, Gonzalez AL, Lu P, Datta PK (2012) Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin. Mol Cancer Ther 11(11):2362–2372

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Davis R, Rizwani W, Banerjee S, Kovacs M, Haura E, Coppola D, Chellappan S (2009) Nicotine promotes tumor growth and metastasis in mouse models of lung cancer. PLoS ONE 4(10):e7524

    PubMed Central  PubMed  Google Scholar 

  184. Spindel ER (2009) Is nicotine the estrogen of lung cancer? Am J Respir Crit Care Med 179(12):1081–1082

    CAS  PubMed  Google Scholar 

  185. Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3(10):733–744

    CAS  PubMed  Google Scholar 

  186. Schuller HM, Orloff M (1998) Tobacco-specific carcinogenic nitrosamines. Ligands for nicotinic acetylcholine receptors in human lung cancer cells. Biochem Pharmacol 55(9):1377–1384

    CAS  PubMed  Google Scholar 

  187. Catassi A, Servent D, Paleari L, Cesario A, Russo P (2008) Multiple roles of nicotine on cell proliferation and inhibition of apoptosis: implications on lung carcinogenesis. Mutat Res 659(3):221–231

    CAS  PubMed  Google Scholar 

  188. Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, et al. (2009) Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer 124(1):36–45

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Lam DC, Girard L, Ramirez R, Chau WS, Suen WS, Sheridan S, et al. (2007) Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res 67(10):4638–4647

    CAS  PubMed  Google Scholar 

  190. Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, et al. (2005) Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 26(7):1182–1195

    CAS  PubMed  Google Scholar 

  191. Maneckjee R, Minna JD (1994) Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ 5(10):1033–1040

    CAS  PubMed  Google Scholar 

  192. Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, et al. (2001) Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 7(7):833–839

    CAS  PubMed  Google Scholar 

  193. Jarzynka MJ, Guo P, Bar-Joseph I, Hu B, Cheng SY (2006) Estradiol and nicotine exposure enhances A549 bronchioloalveolar carcinoma xenograft growth in mice through the stimulation of angiogenesis. Int J Oncol 28(2):337–344

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Westenberger BJ (2009) Evaluation of e-cigarettes: DPATR-FY-09-23. Prepared by U.S. Food and Drug Administration/Center for Drug Evaluation and Research. St Louis, MO

    Google Scholar 

  195. Williams M, Villarreal A, Bozhilov K, Lin S, Talbot P (2013) Metal and silicate particles including nanoparticles are present in electronic cigarette cartomizer fluid and aerosol. PLoS ONE 8(3):e57987

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Goniewicz ML, Knysak J, Gawron M, Kosmider L, Sobczak A, Kurek J, et al. (2014) Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control 23(2):133–139

    PubMed  Google Scholar 

  197. Cobb NK, Abrams DB (2011) E-cigarette or drug-delivery device? Regulating novel nicotine products. N Engl J Med 365(3):193–195

    CAS  PubMed  Google Scholar 

  198. Laugesen M (2008) Safety report on the Ruyan® e-cigarette cartridge and inhaled aerosol. New Zealand Ltd. Christchurch, New Zealand

    Google Scholar 

  199. Vansickel AR, Eissenberg T (2013) Electronic cigarettes: effective nicotine delivery after acute administration. Nicotine Tob Res 15(1):267–270

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Vardavas CI, Anagnostopoulos N, Kougias M, Evangelopoulou V, Connolly GN, Behrakis PK (2012) Short-term pulmonary effects of using an electronic cigarette: impact on respiratory flow resistance, impedance, and exhaled nitric oxide. Chest 141(6):1400–1406

    CAS  PubMed  Google Scholar 

  201. Maunders H, Patwardhan S, Phillips J, Clack A, Richter A (2007) Human bronchial epithelial cell transcriptome: gene expression changes following acute exposure to whole cigarette smoke in vitro. Am J Physiol Lung Cell Mol Physiol 292(5):L1248–1256

    CAS  PubMed  Google Scholar 

  202. Riker CA, Lee K, Darville A, Hahn EJ (2012) E-cigarettes: promise or peril? Nurs Clin North Am 47(1):159–171

    PubMed  Google Scholar 

  203. Trtchounian A, Williams M, Talbot P (2010) Conventional and electronic cigarettes (e-cigarettes) have different smoking characteristics. Nicotine Tob Res 12(9):905–912

    PubMed  Google Scholar 

  204. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation 119(6):1420–1428

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Nieto MA, Cano A (2012) The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Seminars in Cancer Biology 22(5–6):361–368

    CAS  PubMed  Google Scholar 

  206. Chen W, Gao Q, Han S, Pan F, Fan W (2014) The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour Biol 36(2):973–981.

    Google Scholar 

  207. Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Morris SB, Xue YY, et al. (1998) Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J Clin Invest 102(3):465–472

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Arenberg DA, Kunkel SL, Polverini PJ, Glass M, Burdick MD, Strieter RM (1996) Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J Clin Invest 97(12):2792–2802

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Keane MP, Belperio JA, Xue YY, Burdick MD, Strieter RM (2004) Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol 172(5):2853–2860

    CAS  PubMed  Google Scholar 

  210. Wislez M, Fujimoto N, Izzo JG, Hanna AE, Cody DD, Langley RR, et al. (2006) High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res 66(8):4198–4207

    CAS  PubMed  Google Scholar 

  211. Risolino M, Mandia N, Iavarone F, Dardaei L, Longobardi E, Fernandez S, et al. (2014) Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-beta-SMAD3 pathway in non-small cell lung adenocarcinoma. Proc Natl Acad Sci U S A 111(36):E3775–3784

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Ren J, Chen Y, Song H, Chen L, Wang R (2013) Inhibition of ZEB1 reverses EMT and chemoresistance in docetaxel-resistant human lung adenocarcinoma cell line. J Cell Biochem 114(6):1395–1403

    CAS  PubMed  Google Scholar 

  213. Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L, et al. (2005) Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11(24 Pt 1):8686–8698

    CAS  PubMed  Google Scholar 

  214. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, et al. (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65(20):9455–9462

    CAS  PubMed  Google Scholar 

  215. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, et al. (2006) Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 66(2):944–950

    CAS  PubMed  Google Scholar 

  216. Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. (2013) An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 19(1):279–290

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Gomperts BN, Spira A, Massion PP, Walser TC, Wistuba, II, Minna JD, Dubinett SM (2011) Evolving concepts in lung carcinogenesis. Semin Respir Crit Care Med 32(1):32–43

    Google Scholar 

  218. Sullivan JP, Minna JD, Shay JW (2010) Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev 29(1):61–72

    PubMed Central  PubMed  Google Scholar 

  219. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 106(33):13820–13825

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Yu M, Smolen GA, Zhang J, Wittner B, Schott BJ, Brachtel E, et al. (2009) A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev 23(15):1737–1742

    CAS  PubMed Central  PubMed  Google Scholar 

  223. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, et al. (2010) Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12(10):982–992

    PubMed  Google Scholar 

  224. Giannoni E, Bianchini F, Calorini L, Chiarugi P (2011) Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 14(12): 2361–2371

    Google Scholar 

  225. Louie E, Nik S, Chen JS, Schmidt M, Song B, Pacson C, et al. Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res 12(6):R94

    Google Scholar 

  226. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27(9):2059–2068

    CAS  PubMed  Google Scholar 

  227. Pinho AV, Rooman I, Real FX (2011) p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells. Cell Cycle 10(8):1312–1321

    CAS  PubMed  Google Scholar 

  228. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, et al. (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13(3):317–323

    CAS  PubMed Central  PubMed  Google Scholar 

  229. May R, Sureban SM, Hoang N, Riehl TE, Lightfoot SA, Ramanujam R, et al. (2009) Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively. Stem Cells 27(10):2571–2579

    CAS  PubMed Central  PubMed  Google Scholar 

  230. Sureban SM, May R, Ramalingam S, Subramaniam D, Natarajan G, Anant S, Houchen CW (2009) Selective blockade of DCAMKL-1 results in tumor growth arrest by a Let-7a MicroRNA-dependent mechanism. Gastroenterology 137(2):649–659, 659 e641–642

    Google Scholar 

  231. Sureban SM, May R, Lightfoot SA, Hoskins AB, Lerner M, Brackett DJ, et al. DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer Res 71(6):2328–2338

    Google Scholar 

  232. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11(12):1487–1495

    Google Scholar 

  233. Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G, Firat E, et al. (2011) The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J 30(4):770–782

    CAS  PubMed Central  PubMed  Google Scholar 

  234. Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL, Damiani LA, et al. (2011) EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res 71(8):3087–3097

    CAS  PubMed Central  PubMed  Google Scholar 

  235. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312

    CAS  PubMed  Google Scholar 

  236. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, et al. (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361

    CAS  PubMed Central  PubMed  Google Scholar 

  237. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, et al. (2008) Systemic spread is an early step in breast cancer. Cancer cell 13(1):58–68

    PubMed  Google Scholar 

  238. Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H (2008) Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321(5897):1841–1844

    CAS  PubMed Central  PubMed  Google Scholar 

  239. Wyckoff JB, Jones JG, Condeelis JS, Segall JE (2000) A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res 60(9):2504–2511

    CAS  PubMed  Google Scholar 

  240. Wang W, Wyckoff JB, Frohlich VC, Oleynikov Y, Huttelmaier S, Zavadil J, et al. (2002) Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res 62(21):6278–6288

    CAS  PubMed  Google Scholar 

  241. Beaty BT, Wang Y, Bravo-Cordero JJ, Sharma VP, Miskolci V, Hodgson L, Condeelis J (2014) Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. J Cell Biol 205(5):737–751

    CAS  PubMed Central  PubMed  Google Scholar 

  242. Jung HY, Fattet L, Yang J (2015) Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res 21(5): 962–968

    Google Scholar 

  243. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241–254

    CAS  PubMed  Google Scholar 

  244. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139(5):891–906

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS (2012) Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition. Mol Biol Cell 23(5):781–791

    CAS  PubMed Central  PubMed  Google Scholar 

  246. Gill BJ, Gibbons DL, Roudsari LC, Saik JE, Rizvi ZH, Roybal JD, et al. (2012) A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. Cancer Res 72(22):6013–6023

    CAS  PubMed Central  PubMed  Google Scholar 

  247. Buckley ST, Davies AM, Ehrhardt C (2011) Atomic force microscopy and high-content analysis: two innovative technologies for dissecting the relationship between epithelial-mesenchymal transition-related morphological and structural alterations and cell mechanical properties. Methods Mol Biol 784:197–208

    CAS  PubMed  Google Scholar 

  248. Shibue T, Brooks MW, Inan MF, Reinhardt F, Weinberg RA (2012) The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov 2(8):706–721

    CAS  PubMed Central  PubMed  Google Scholar 

  249. Wu TH, Chou YW, Chiu PH, Tang MJ, Hu CW, Yeh ML (2014) Validation of the effects of TGF-beta1 on tumor recurrence and prognosis through tumor retrieval and cell mechanical properties. Cancer Cell Int 14(1):20

    PubMed Central  PubMed  Google Scholar 

  250. Zhou Z, Zheng C, Li S, Zhou X, Liu Z, He Q, et al. (2013) AFM nanoindentation detection of the elastic modulus of tongue squamous carcinoma cells with different metastatic potentials. Nanomedicine 9(7):864–874

    CAS  PubMed  Google Scholar 

  251. Osborne LD, Li GZ, How T, O’Brien ET, Blobe GC, Superfine R, Mythreye K (2014) TGF-beta regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Mol Biol Cell 25(22):3528–3540

    PubMed Central  PubMed  Google Scholar 

  252. Creighton CJ, Gibbons DL, Kurie JM (2013) The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective. Cancer Manag Res 5:187–195

    PubMed Central  PubMed  Google Scholar 

  253. Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, et al. (2011) Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol 29(32):4320–4326

    CAS  PubMed  Google Scholar 

  254. Scagliotti GV, Ilaria R, Jr., Novello S, von Pawel J, Fischer JR, Ermisch S, et al. (2012) Tasisulam sodium (LY573636 sodium) as third-line treatment in patients with unresectable, metastatic non-small-cell lung cancer: a phase-II study. J Thorac Oncol 7(6):1053–1057

    CAS  PubMed  Google Scholar 

  255. Harada D, Takigawa N, Kiura K (2014) The role of STAT3 in non-small cell lung cancer. Cancers (Basel) 6(2):708–722

    CAS  Google Scholar 

  256. Kim YJ, Choi WI, Jeon BN, Choi KC, Kim K, Kim TJ, et al. (2014) Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology 322:23–33

    CAS  PubMed  Google Scholar 

  257. Gadgeel SM, Ruckdeschel JC, Heath EI, Heilbrun LK, Venkatramanamoorthy R, Wozniak A (2007) Phase II study of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with platinum refractory non-small cell lung cancer (NSCLC). J Thorac Oncol 2(4):299–305

    PubMed  Google Scholar 

  258. O’Byrne KJ, Danson S, Dunlop D, Botwood N, Taguchi F, Carbone D, Ranson M (2007) Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer. J Clin Oncol 25(22):3266–3273

    PubMed  Google Scholar 

  259. Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, et al. (2014) Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res 20(10):2714–2726

    CAS  PubMed  Google Scholar 

  260. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD (2008) Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 105(39):14867–14872

    CAS  PubMed Central  PubMed  Google Scholar 

  261. Kiesslich T, Pichler M, Neureiter D (2013) Epigenetic control of epithelial-mesenchymal-transition in human cancer. Mol Clin Oncol 1(1):3–11

    PubMed Central  PubMed  Google Scholar 

  262. Cieslik M, Hoang SA, Baranova N, Chodaparambil S, Kumar M, Allison DF, et al. (2013) Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition. Epigenetics Chromatin 6(1):28

    CAS  PubMed Central  PubMed  Google Scholar 

  263. Carmona FJ, Davalos V, Vidal E, Gomez A, Heyn H, Hashimoto Y, et al. (2014) A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition. Cancer Res 74(19):5608–5619

    CAS  PubMed  Google Scholar 

  264. Roll JD, Rivenbark AG, Sandhu R, Parker JS, Jones WD, Carey LA, et al. (2013) Dysregulation of the epigenome in triple-negative breast cancers: basal-like and claudin-low breast cancers express aberrant DNA hypermethylation. Exp Mol Pathol 95(3):276–287

    CAS  PubMed  Google Scholar 

  265. Muqbil I, Wu J, Aboukameel A, Mohammad RM, Azmi AS (2014) Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition? Semin Cancer Biol 27:39–45

    CAS  PubMed  Google Scholar 

  266. Neggers JE, Vercruysse T, Jacquemyn M, Vanstreels E, Baloglu E, Shacham S, et al. (2015) Identifying drug-target selectivity of small-molecule CRM1/XPO1 inhibitors by CRISPR/Cas9 genome editing. Chem Biol 22(1): 107–116

    Google Scholar 

  267. Braeutigam C, Rago L, Rolke A, Waldmeier L, Christofori G, Winter J (2014) The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion. Oncogene 33(9):1082–1092

    CAS  PubMed  Google Scholar 

  268. Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, et al. (2010) An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 29(19):3286–3300

    CAS  PubMed Central  PubMed  Google Scholar 

  269. Lu ZX, Huang Q, Park JW, Shen S, Lin L, Tokheim CJ, et al. (2015) Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. 13(2): 305–318

    Google Scholar 

  270. Tavanez JP, Valcarcel J (2010) A splicing mastermind for EMT. EMBO J 29(19):3217–3218

    CAS  PubMed Central  PubMed  Google Scholar 

  271. Dubinett SM, Spira A (2013) Challenge and opportunity of targeted lung cancer chemoprevention. J Clin Oncol 31(33):4169–4171

    CAS  PubMed  Google Scholar 

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Acknowledgments

Research reported in this publication was supported in part by funding from the National Cancer Institute (#T32-CA009120-36 and #U01CA152751), Department of Veteran Affairs (#2I01BX000359-05A1), and Tobacco-Related Disease Research Program (#18FT-0060 and #20KT-0055).

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  1. Division of Pulmonary & Critical Care Medicine, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA

    Asst. Prof. Tonya C. Walser PhD, Stacy J. Park PhD & Steven M. Dubinett MD

  2. Division of Thoracic Surgery, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA

    Asst. Prof. Jane Yanagawa MD

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  1. Asst. Prof. Tonya C. Walser PhD
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  2. Stacy J. Park PhD
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  3. Asst. Prof. Jane Yanagawa MD
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  4. Steven M. Dubinett MD
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Correspondence to Steven M. Dubinett MD .

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    Steven M. Dubinett

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Walser, T., Park, S., Yanagawa, J., Dubinett, S. (2015). Inflammation and Lung Cancer: The Role of Epithelial–Mesenchymal Transition. In: Dubinett, S. (eds) Inflammation and Lung Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2724-1_2

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