DOI QR코드

DOI QR Code

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

  • Ping, Wei (Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) ;
  • Jiang, Wen-Yang (Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) ;
  • Chen, Wen-Shu (Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) ;
  • Sun, Wei (Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) ;
  • Fu, Xiang-Ning (Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology)
  • Published : 2013.06.30

Abstract

Object: To detect expression of hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and lysyl oxidase (LOX) in non-small cell lung cancer (NSCLC) and explore their roles in prognosis. Methods: The mRNA levels of HIF-$1{\alpha}$ and LOX were investigated by real-time reverse-transcriptase polymerase chain reaction in 40 cases of tumour and paired normal tissues. In addition, protein expression of HIF-$1{\alpha}$ and LOX was examined by immunohistochemistry in 82 cases of tumour and 45 paired normal tissues. The relationship between HIF-$1{\alpha}$ or LOX and clinicopathologic characteristics, as well as the correlation between HIF-$1{\alpha}$ and LOX, were also examined. Kaplan-Meier survival curves and the log-rank test were used to analyze progression-free survival. Results: HIF-$1{\alpha}$ or LOX mRNA levels in tumor tissues was significantly higher than those in paired normal tissues (p<0.01). Positive HIF-$1{\alpha}$ or LOX protein expression in tumor tissues was noted in 46/82 (56.1%) and 49/82 (59.8%) of the cases, respectively, being significantly higher than those in paired normal tissues (p<0.05). There was significant correlation between the expression of HIF-$1{\alpha}$ or LOX and tumor size, lymph node metastasis and pathological stage (p<0.05). The expression of HIF-$1{\alpha}$ and LOX had a significant inverse impact on survival of patients with NSCLC. Conclusion: HIF-$1{\alpha}$ and LOX may play a pivotal role in the development of NSCLC, and may act in synergy to promote the progression of NSCLC.

Keywords

HIF-$1{\alpha}$;LOX;NSCLC;prognosis

References

  1. al-Kattan K, Sepsas E, Fountain SW, et al (1997). Disease recurrence after resection for stage I lung cancer. Eur J Cardiothorac Surg, 12, 380-4. https://doi.org/10.1016/S1010-7940(97)00198-X
  2. Albinger-Hegyi A, Stoeckli SJ, Schmid S, et al (2010). Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC). Int J Cancer, 126, 2653-62.
  3. Bachtiary B, Schindl M, Potter R, et al (2003). Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res, 9, 2234-40.
  4. Baker AM, Bird D, Lang G, et al (2013). Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene, 32, 1863-8. https://doi.org/10.1038/onc.2012.202
  5. Birner P, Schindl M, Obermair A, et al (2000). Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res, 60, 4693-6.
  6. Cheng JC, Klausen C, Leung PC (2013). Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett, 329, 197-206. https://doi.org/10.1016/j.canlet.2012.10.029
  7. Erler JT, Bennewith KL, Nicolau M, et al (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440, 1222-6. https://doi.org/10.1038/nature04695
  8. Gao Y, Xiao Q, Ma H, et al (2010). LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA, 107, 18892-7. https://doi.org/10.1073/pnas.1004952107
  9. Giatromanolaki A, Koukourakis MI, Sivridis E, et al (2001). Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer, 85, 881-90. https://doi.org/10.1054/bjoc.2001.2018
  10. Gu CD, Osaki T, Oyama T, et al (2002). Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected nonsmall cell lung cancer: impact on recurrence and Survival. Ann Surg, 235, 133-9. https://doi.org/10.1097/00000658-200201000-00017
  11. Hiraki M, Kitajima Y, Kai K, et al (2012). Knockdown of hypoxia-inducible factor-1alpha accelerates peritoneal dissemination via the upregulation of MMP-1 expression in gastric cancer cell lines. Exp Ther Med, 4, 355-62.
  12. Hirami Y, Aoe M, Tsukuda K, et al (2004). Relation of epidermal growth factor receptor, phosphorylated-Akt, and hypoxiainducible factor-1alpha in non-small cell lung cancers. Cancer Lett, 214, 157-64. https://doi.org/10.1016/j.canlet.2004.04.028
  13. Hung JJ, Yang MH, Hsu HS, et al (2009). Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax, 64, 1082-9. https://doi.org/10.1136/thx.2009.115691
  14. Lapointe J, Li C, Higgins JP, et al (2004). Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA, 101, 811-6. https://doi.org/10.1073/pnas.0304146101
  15. Lee CH, Lee MK, Kang CD, et al (2003). Differential expression of hypoxia inducible factor-1 alpha and tumor cell proliferation between squamous cell carcinomas and adenocarcinomas among operable non-small cell lung carcinomas. J Korean Med Sci, 18, 196-203. https://doi.org/10.3346/jkms.2003.18.2.196
  16. Le QT, Kong C, Lavori PW, et al (2007). Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys, 69, 167-75. https://doi.org/10.1016/j.ijrobp.2007.01.071
  17. Park S, Ha SY, Cho HY, et al (2011). Prognostic implications of hypoxia-inducible factor-1alpha in epidermal growth factor receptor-negative non-small cell lung cancer. Lung Cancer, 72, 100-7. https://doi.org/10.1016/j.lungcan.2010.08.005
  18. Payne SL, Hendrix MJ, Kirschmann DA (2007). Paradoxical roles for lysyl oxidases in cancer--a prospect. J Cell Biochem, 101, 1338-54. https://doi.org/10.1002/jcb.21371
  19. Pez F, Dayan F, Durivault J, et al (2011). The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. Cancer Res, 71, 1647-57. https://doi.org/10.1158/0008-5472.CAN-10-1516
  20. Sahlgren C, Gustafsson MV, Jin S, et al (2008). Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA, 105, 6392-7. https://doi.org/10.1073/pnas.0802047105
  21. Schietke R, Warnecke C, Wacker I, et al (2010). The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem, 285, 6658-69. https://doi.org/10.1074/jbc.M109.042424
  22. Schito L, Rey S, Tafani M, et al (2012). Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA, 109, E2707-16. https://doi.org/10.1073/pnas.1214019109
  23. Siegel R, DeSantis C, Virgo K, et al (2012). Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin, 62, 220-41. https://doi.org/10.3322/caac.21149
  24. Siegel R, Ward E, Brawley O, et al (2011). Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin, 61, 212-36. https://doi.org/10.3322/caac.20121
  25. Stassar MJ, Devitt G, Brosius M, et al (2001). Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer, 85, 1372-82. https://doi.org/10.1054/bjoc.2001.2074
  26. Stewart GD, Nanda J, Brown DJ, et al (2009). NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway. Int J Cancer, 124, 223-32. https://doi.org/10.1002/ijc.23934
  27. Swinson DE, Jones JL, Cox G, et al (2004). Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer, 111, 43-50. https://doi.org/10.1002/ijc.20052
  28. Tammali R, Saxena A, Srivastava SK, et al (2011). Aldose reductase inhibition prevents hypoxia-induced increase in hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) by regulating 26 S proteasome-mediated protein degradation in human colon cancer cells. J Biol Chem, 286, 24089-100. https://doi.org/10.1074/jbc.M111.219733
  29. Volm M, Koomagi R (2000). Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res, 20, 1527-33.
  30. Wei L, Song XR, Sun JJ, et al (2012). Lysyl oxidase may play a critical role in hypoxia-induced NSCLC cells invasion and migration. Cancer Biother Radiopharm, 27, 672-7. https://doi.org/10.1089/cbr.2012.1241
  31. Wilgus ML, Borczuk AC, Stoopler M, et al (2011). Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival. Cancer, 117, 2186-91. https://doi.org/10.1002/cncr.25768
  32. Wong CC, Gilkes DM, Zhang H, et al (2011). Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA, 108, 16369-74. https://doi.org/10.1073/pnas.1113483108
  33. Wong CC, Zhang H, Gilkes DM, et al (2012). Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med (Berl), 90, 803-15. https://doi.org/10.1007/s00109-011-0855-y
  34. Woznick AR, Braddock AL, Dulai M, et al (2005). Lysyl oxidase expression in bronchogenic carcinoma. Am J Surg, 189, 297-301. https://doi.org/10.1016/j.amjsurg.2004.11.031
  35. Zhang JJ, Wu HS, Wang L, et al (2010). Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma. World J Gastroenterol, 16, 2881-8. https://doi.org/10.3748/wjg.v16.i23.2881
  36. Zhao T, Gao S, Wang X, et al (2012). Hypoxia-inducible factor-1alpha regulates chemotactic migration of pancreatic ductal adenocarcinoma cells through directly transactivating the CX3CR1 gene. PLoS One, 7, e43399. https://doi.org/10.1371/journal.pone.0043399
  37. Zhong H, De Marzo AM, Laughner E, et al (1999). Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res, 59, 5830-5.

Cited by

  1. The hypoxic tumor microenvironment: driving the tumorigenesis of non-small-cell lung cancer vol.10, pp.16, 2014, https://doi.org/10.2217/fon.14.201
  2. Upregulation of HIF-1α by Hypoxia Protect Neuroblastoma Cells from Apoptosis by Promoting Survivin Expression vol.15, pp.19, 2014, https://doi.org/10.7314/APJCP.2014.15.19.8251
  3. Influence of Ionizing Radiation on Ovarian Carcinoma SKOV-3 Xenografts in Nude Mice under Hypoxic Conditions vol.15, pp.5, 2014, https://doi.org/10.7314/APJCP.2014.15.5.2353
  4. Correlation between tumor size and blood volume in lung tumors: a prospective study on dual-energy gemstone spectral CT imaging vol.55, pp.5, 2014, https://doi.org/10.1093/jrr/rru026
  5. LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation vol.10, pp.3, 2015, https://doi.org/10.1371/journal.pone.0119781
  6. Immunohistochemistry-based prognostic biomarkers in NSCLC: novel findings on the road to clinical use? vol.15, pp.4, 2015, https://doi.org/10.1586/14737159.2015.1002772
  7. Hypoxia Induced High Expression of Thioredoxin Interacting Protein (TXNIP) in Non-small Cell Lung Cancer and its Prognostic Effect vol.16, pp.7, 2015, https://doi.org/10.7314/APJCP.2015.16.7.2953
  8. Immunohistochemistry with a novel mutation-specific monoclonal antibody as a screening tool for the EGFR L858R mutational status in primary lung adenocarcinoma vol.36, pp.2, 2015, https://doi.org/10.1007/s13277-014-2643-0
  9. Lysyl oxidase mediates hypoxia-induced radioresistance in non-small cell lung cancer A549 cells vol.241, pp.4, 2016, https://doi.org/10.1177/1535370215609694
  10. Clinicopathological and prognostic significance of hypoxia-inducible factor-1 alpha in lung cancer: a systematic review with meta-analysis vol.36, pp.3, 2016, https://doi.org/10.1007/s11596-016-1586-7