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Tumor Biology

, Volume 36, Issue 3, pp 1493–1502 | Cite as

NADPH oxidase 1-dependent ROS is crucial for TLR4 signaling to promote tumor metastasis of non-small cell lung cancer

  • Xiyu Liu
  • Changyan Pei
  • Song Yan
  • Guifeng Liu
  • Gang Liu
  • Wenqing Chen
  • Youbin Cui
  • Yahui Liu
Research Article

Abstract

Recent evidence demonstrated an enhanced metastasis of non-small cell lung cancer (NSCLC) cells induced by lipopolysaccharide (LPS) stimulation, which reflected an important role of inflammation in tumor progression. However, the underlying mechanisms still remain unclear. Here, we evaluated the potential role of reactive oxygen species (ROS) in Toll-like receptor 4 (TLR4) signaling enhanced NSCLC metastasis. NSCLC cells were isolated from clinical surgical tissues. We found that LPS stimulation of NSCLC cells facilitates their metastasis that was accompanied by increased ROS production and could be abrogated by ROS inhibition. NADPH oxidase was essential for TLR4 signaling-enhanced NSCLC metastasis. Elevated NADPH oxidase 1 (NOX1) expression by LPS stimulation was observed. Blockade of NOX1 with ML171 alleviated enhanced NSCLC metastasis by TLR4 signaling. Enforced NOX1 expression promoted TLR4 signaling-enhanced NSCLC metastasis, while decreased NOX1 expression inhibited TLR4 signaling-enhanced NSCLC metastasis. Further, NOX1 could regulate the expression of CXCR4 and matrix metallopeptidase 9 (MMP9) in NSCLC cells. NOX1 expression in tumor tissues was correlated with TLR4 expression and clinical stages in NSCLC patients. Finally, inhibition of NOX1/ROS prevented enhanced lung tumor burdens of NSCLC by LPS-induced acute lung infection. Our findings demonstrated a crucial role of NOX1-dependent ROS for TLR4 signaling to enhance the metastasis of NSCLC, which could further the understanding of NSCLC pathogenesis and helpful for developing novel therapeutics for NSCLC.

Keywords

Non-small cell lung cancer TLR4 NADPH oxidase 1 Tumor metastasis 

Notes

Acknowledgments

This work was supported by the Jilin Province Science Foundation for Youths (No. 20140520026JH) and Changchun Social Development Plan of Science and Technology (No. 3D513A343428).

Conflicts of interest

None

References

  1. 1.
    Kanne JP. Screening for lung cancer: what have we learned? AJR Am J Roentgenol. 2014;202:530–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Govindan R, Bogart J, Vokes EE. Locally advanced non-small cell lung cancer: the past, present, and future. J Thorac Oncol. 2008;3:917–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.CrossRefPubMedGoogle Scholar
  4. 4.
    Li Q, Han Y, Fei G, Guo Z, Ren T, Liu Z. IL-17 promoted metastasis of non-small-cell lung cancer cells. Immunol Lett. 2012;148:144–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Suleiman AA, Nogova L, Fuhr U. Modeling NSCLC progression: recent advances and opportunities available. AAPS J. 2013;15:542–50.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dang S, Peng Y, Ye L, Wang Y, Qian Z, Chen Y, et al. Stimulation of TLR4 by LMW-HA induces metastasis in human papillary thyroid carcinoma through CXCR7. Clin Dev Immunol. 2013;2013:712561.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Zhang D, Li YH, Mi M, Jiang FL, Yue ZG, Sun Y, et al. Modified apple polysaccharides suppress the migration and invasion of colorectal cancer cells induced by lipopolysaccharide. Nutr Res. 2013;33:839–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Hsu RY, Chan CH, Spicer JD, Rousseau MC, Giannias B, Rousseau S, et al. LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res. 2011;71:1989–98.CrossRefPubMedGoogle Scholar
  9. 9.
    Liao SJ, Zhou YH, Yuan Y, Li D, Wu FH, Wang Q, et al. Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration. Breast Cancer Res Treat. 2012;133:853–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Jing YY, Han ZP, Sun K, Zhang SS, Hou J, Liu Y, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhan Z, Xie X, Cao H, Zhou X, Zhang XD, Fan H, et al. Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination. Autophagy. 2014;10:257–68.CrossRefPubMedGoogle Scholar
  12. 12.
    Li C, Li H, Jiang K, Li J, Gai X. TLR4 signaling pathway in mouse Lewis lung cancer cells promotes the expression of TGF-β1 and IL-10 and tumor cells migration. Biomed Mater Eng. 2014;24:869–75.PubMedGoogle Scholar
  13. 13.
    Ritsick DR, Edens WA, McCoy JW, Lambeth JD. The use of model systems to study biological functions of Nox/Duox enzymes. Biochem Soc Symp. 2004;71:85–96.CrossRefGoogle Scholar
  14. 14.
    Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci U S A. 2002;99:715–20.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chamulitrat W. Role of gp91phox homolog nox1 in induction of premalignant spindle phenotypes of HPV 16 E6/E7-immortalized human keratinocytes. Sci World J. 2010;10:1435–49.CrossRefGoogle Scholar
  16. 16.
    Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 2008;266:37–52.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Coso S, Harrison I, Harrison CB, Vinh A, Sobey CG, Drummond GR, et al. NADPH oxidases as regulators of tumor angiogenesis: current and emerging concepts. Antioxid Redox Signal. 2012;16:1229–47.CrossRefPubMedGoogle Scholar
  18. 18.
    Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007;67:10823–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Wen Z, Xu L, Chen X, Xu W, Yin Z, Gao X, et al. Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway. J Immunol. 2013;190:5411–22.CrossRefPubMedGoogle Scholar
  20. 20.
    Yan L, Cai Q, Xu Y. The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin Cancer Res. 2013;19:4706–16.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fu HY, Li C, Yang W, Gai XD, Jia T, Lei YM, et al. FOXP3 and TLR4 protein expression are correlated in non-small cell lung cancer: implications for tumor progression and escape. Acta Histochem. 2013;115:151–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang YB, He FL, Fang M, Hua TF, Hu BD, Zhang ZH, et al. Increased expression of Toll-like receptors 4 and 9 in human lung cancer. Mol Biol Rep. 2009;36:1475–81.CrossRefPubMedGoogle Scholar
  23. 23.
    Hattar K, Savai R, Subtil FS, Wilhelm J, Schmall A, Lang DS, et al. Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation. Cancer Immunol Immunother. 2013;62:309–20.CrossRefPubMedGoogle Scholar
  24. 24.
    O’Leary DP, Bhatt L, Woolley JF, Gough DR, Wang JH, Cotter TG, et al. TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1. PLoS One. 2012;7:e44176.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Maraldi T. Natural compounds as modulators of NADPH oxidases. Oxidative Med Cell Longev. 2013;2013:271602.CrossRefGoogle Scholar
  26. 26.
    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.CrossRefPubMedGoogle Scholar
  27. 27.
    Griffith B, Pendyala S, Hecker L, Lee PJ, Natarajan V, Thannickal VJ. NOX enzymes and pulmonary disease. Antioxid Redox Signal. 2009;11:2505–16.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cheng SE, Lee IT, Lin CC, Wu WL, Hsiao LD, Yang CM. ATP mediates NADPH oxidase/ROS generation and COX-2/PGE2 expression in A549 cells: role of P2 receptor-dependent STAT3 activation. PLoS One. 2013;8:e54125.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cattaneo F, Iaccio A, Guerra G, Montagnani S, Ammendola R. NADPH-oxidase-dependent reactive oxygen species mediate EGFR transactivation by FPRL1 in WKYMVm-stimulated human lung cancer cells. Free Radic Biol Med. 2011;51:1126–36.CrossRefPubMedGoogle Scholar
  30. 30.
    Kamata T. Roles of Nox1 and other Nox isoforms in cancer development. Cancer Sci. 2009;100:1382–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Laurent E, McCoy 3rd JW, Macina RA, Liu W, Cheng G, Robine S, et al. Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras. Int J Cancer. 2008;123:100–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Komatsu D, Kato M, Nakayama J, Miyagawa S, Kamata T. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. Oncogene. 2008;27:4724–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Kim JS, Yeo S, Shin DG, Bae YS, Lee JJ, Chin BR, et al. Glycogen synthase kinase 3beta and beta-catenin pathway is involved in toll-like receptor 4-mediated NADPH oxidase 1 expression in macrophages. FEBS J. 2010;277:2830–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Shinohara M, Adachi Y, Mitsushita J, Kuwabara M, Nagasawa A, Harada S, et al. Reactive oxygen generated by NADPH oxidase 1 (Nox1) contributes to cell invasion by regulating matrix metalloprotease-9 production and cell migration. J Biol Chem. 2010;285:4481–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Choi YH, Burdick MD, Strieter BA, Mehrad B, Strieter RM. CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells. Mol Cancer Res. 2014;12:38–47.CrossRefPubMedGoogle Scholar
  36. 36.
    Pei J, Lou Y, Zhong R, Han B. MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer. Tumour Biol. 2014; 35:6673–8Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Chest Surgery, The First Bethune HospitalJilin UniversityChangchun CityChina
  2. 2.Department of Medical AdministrationJilin Province People’s HospitalChangchunChina
  3. 3.Department of Chest SurgeryJilin Province Cancer HospitalChangchunChina
  4. 4.Department of RadiologyChina-Japan Union Hospital of Jilin UniversityChangchunChina
  5. 5.Department of Hepatobiliary and Pancreatic Surgery, The First Bethune HospitalJilin UniversityChangchun CityChina

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