Tumor Biology

, Volume 36, Issue 4, pp 3075–3084 | Cite as

Downregulation of Kruppel-like factor 2 is associated with poor prognosis for nonsmall-cell lung cancer

  • Li Yin
  • Ji-peng Wang
  • Tong-peng Xu
  • Wen-ming Chen
  • Ming-de Huang
  • Rui Xia
  • Xin-xin Liu
  • Rong Kong
  • Ming Sun
  • Er-bao Zhang
  • Yong-qian Shu
Research Article


Kruppel-like factor 2 (KLF2) expression is diminished in many malignancies. However, its expression and role in nonsmall-cell lung cancer (NSCLC) remain unknown. In this study, we found that KLF2 levels were decreased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, tumor size, and lymph node metastasis. Moreover, patients with low levels of KLF2 expression had a relatively poor prognosis. Furthermore, knockdown of KLF2 expression by siRNA could promote cell proliferation, while ectopic expression of KLF2 inhibited cell proliferation and promoted apoptosis in NSCLC cells partly via regulating CDKN1A/p21 and CDKN2B/p15 protein expression. Our findings present that decreased KLF2 could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and apoptosis.


Kruppel-like factor 2 (KLF2) Poor prognosis Proliferation Apoptosis CDKN1A/p21 CDKN2B/p15 



This study was supported by the National Natural Science Foundation of China (81172140, 81272532), Jiangsu Province Clinical Science and Technology projects (Clinical Research Center, BL2012008) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine, JX10231801).

Conflicts of interest



  1. 1.
    Lee YJ, Kim JH, Kim SK, Ha SJ, Mok TS, Mitsudomi T, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer J Iaslc. 2011;72:9–15.CrossRefGoogle Scholar
  2. 2.
    Sozzi G: Molecular biology of lung cancer. Eur J Cancer. 2001;37 Suppl 7:63–73Google Scholar
  3. 3.
    Fenech M. The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis. Mutagenesis. 2005;20:255–69.CrossRefPubMedGoogle Scholar
  4. 4.
    Udler M, Maia AT, Cebrian A, Brown C, Greenberg D, Shah M, et al. Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. J Clin Oncol. 2007;25:3015–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Komori T, Takemasa I, Yamasaki M, Motoori M, Kato T, Kikkawa N, et al. Gene expression of colorectal cancer: preoperative genetic diagnosis using endoscopic biopsies. Int J Oncol. 2008;32:367–75.PubMedGoogle Scholar
  6. 6.
    Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. Krüppel-like transcription factors: a functional family. Int J Biochem Cell Biol. 2008;40:1996–2001.CrossRefPubMedGoogle Scholar
  7. 7.
    Suske G, Bruford E, Philipsen S. Mammalian SP/KLF transcription factors: bring in the family. Genomics. 2005;85:551–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Kaczynski J, Cook T, Urrutia R. Sp1- and Krüppel-like transcription factors. Genome Biol. 2003;4:206.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Simmen RC, Pabona JM, Velarde MC, Simmons C, Rahal O, Simmen FA. The emerging role of Kruppel-like factors in endocrine-responsive cancers of female reproductive tissues. J Endocrinol. 2010;204:223–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem. 1996;271:20009–17.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B. A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem. 1996;271:31384–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Benzeno S, Narla G, Allina J, Cheng GZ, Reeves HL, Banck MS, et al. Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Cancer Res. 2004;64:3885–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Lee JS, Yu Q, Shin JT, Sebzda E, Bertozzi C, Chen M, et al. Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev Cell. 2006;11:845–57.CrossRefPubMedGoogle Scholar
  14. 14.
    Kuo CT, Veselits ML, Barton KP, Lu MM, Clendenin C, Leiden JM. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev. 1997;11:2996–3006.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wani MA, Means RJ, Lingrel JB. Loss of LKLF function results in embryonic lethality in mice. Transgenic Res. 1998;7:229–38.CrossRefPubMedGoogle Scholar
  16. 16.
    Chiplunkar AR, Lung TK, Alhashem Y, Koppenhaver BA, Salloum FN, Kukreja RC, et al. Kruppel-like factor 2 is required for normal mouse cardiac development. PLoS One. 2013;8:e54891.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kuo CT, Veselits ML, Leiden JM. LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science. 1997;277:1986–90.CrossRefPubMedGoogle Scholar
  18. 18.
    Weinreich MA, Takada K, Skon C, Reiner SL, Jameson SC, Hogquist KA. KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity. 2009;31:122–30.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Taniguchi H, Jacinto FV, Villanueva A, Fernandez AF, Yamamoto H, Carmona FJ, et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2011;31:1988–94.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Uchida D, Onoue T, Begum NM, Kuribayashi N, Tomizuka Y, Tamatani T, et al. Vesnarinone downregulates CXCR4 expression via upregulation of Kruppel-like factor 2 in oral cancer cells. Mol Cancer. 2009;8:62.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cotterman R, Knoepfler PS. N-Myc regulates expression of pluripotency genes in neuroblastoma including lif, klf2, klf4, and lin28b. PLoS One. 2009;4:e5799.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wu J, Lingrel JB. KLF2 inhibits Jurkat T leukemia cell growth via upregulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1. Oncogene. 2004;23:8088–96.CrossRefPubMedGoogle Scholar
  23. 23.
    Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 1998;12:2984–91.CrossRefPubMedGoogle Scholar
  24. 24.
    Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127:265–75.CrossRefPubMedGoogle Scholar
  25. 25.
    Abbas T, Dutta A. P21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A. Cyclin-binding motifs are essential for the function of p21CIP1. Mol Cell Biol. 1996;16:4673–82.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Li Yin
    • 1
  • Ji-peng Wang
    • 2
  • Tong-peng Xu
    • 1
  • Wen-ming Chen
    • 1
  • Ming-de Huang
    • 3
  • Rui Xia
    • 4
  • Xin-xin Liu
    • 5
  • Rong Kong
    • 5
  • Ming Sun
    • 4
  • Er-bao Zhang
    • 4
  • Yong-qian Shu
    • 1
  1. 1.Department of Oncologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Respiratory Medicine, Huai’an First People’s HospitalNanjing Medical UniversityJiangsuChina
  3. 3.Department of Medical Oncology, Huai’an First People’s HospitalNanjing Medical UniversityJiangsuChina
  4. 4.Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjingChina
  5. 5.Department of Gastrointestinal Surgery, Subei People’s Hospital of Jiangsu ProvinceYangzhou UniversityYangzhouChina

Personalised recommendations