Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
December-2014 Volume 32 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
December-2014 Volume 32 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

  • Authors:
    • Na Liu
    • Yafang Wang
    • Yongan Zhou
    • Hailin Pang
    • Jing Zhou
    • Pei Qian
    • Lili Liu
    • Helong Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, P.R. China, Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
  • Pages: 2397-2404
    |
    Published online on: September 18, 2014
       https://doi.org/10.3892/or.2014.3495
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Krüppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial‑mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter. In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Chaffer CL and Weinberg RA: A perspective on cancer cell metastasis. Science. 331:1559–1564. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Carmeliet P, Dor Y, Herbert JM, et al: Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394:485–490. 1998.

3 

Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr and Pavletich NP: Structure of an HIF-1α-pVHL complex: hydroxy-proline recognition in signaling. Science. 296:1886–1889. 2002.

4 

Liu L, Sun L, Zhao P, et al: Hypoxia promotes metastasis in human gastric cancer by up-regulating the 67-kDa laminin receptor. Cancer Sci. 101:1653–1660. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Liu L, Zhang H, Sun L, et al: ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer. 127:820–829. 2010.PubMed/NCBI

6 

Wang Y, Li Z, Zhang H, et al: HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer. Cancer Biol Ther. 10:376–382. 2010.

7 

Liu L, Ning X, Sun L, et al: Hypoxia-inducible factor-1α contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 99:121–128. 2008.

8 

Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar

9 

Lundgren K, Nordenskjöld B and Landberg G: Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. Br J Cancer. 101:1769–1781. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Yang MH, Wu MZ, Chiou SH, et al: Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol. 10:295–305. 2008.

11 

Yang MH and Wu KJ: TWIST activation by hypoxia inducible factor-1 (HIF-1): implications in metastasis and development. Cell Cycle. 7:2090–2096. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Liu L, Liu N, Xu M, et al: Lentivirus-delivered Krüppel-like factor 8 small interfering RNA inhibits gastric cancer cell growth in vitro and in vivo. Tumour Biol. 33:53–61. 2012.

13 

Wang X and Zhao J: KLF8 transcription factor participates in oncogenic transformation. Oncogene. 26:456–461. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Wang X, Zheng M, Liu G, et al: Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 67:7184–7193. 2007.

15 

Fu WJ, Li JC, Wu XY, et al: Small interference RNA targeting Krüppel-like factor 8 inhibits the renal carcinoma 786-0 cells growth in vitro and in vivo. J Cancer Res Clin Oncol. 136:1255–1265. 2010.

16 

Fink T, Kazlauskas A, Poellinger L, Ebbesen P and Zachar V: Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood. 99:2077–2083. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Shah MA and Ajani JA: Gastric cancer - an enigmatic and heterogeneous disease. JAMA. 303:1753–1754. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar

19 

Hu JH, Navas P, Cao H, Stamatoyannopoulos G and Song CZ: Systematic RNAi studies on the role of Sp/KLF factors in globin gene expression and erythroid differentiation. J Mol Biol. 366:1064–1073. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Sun Z, Han Q, Zhou N, et al: MicroRNA-9 enhances migration and invasion through KLF17 in hepatocellular carcinoma. Mol Oncol. 7:884–894. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Deep G, Jain AK, Ramteke A, et al: SNAI1 is critical for the aggressiveness of prostate cancer cells with low E-cadherin. Mol Cancer. 13:372014. View Article : Google Scholar : PubMed/NCBI

22 

Chan SW, Kallarakkal TG and Abraham MT: Changed expression of E-cadherin and galectin-9 in oral squamous cell carcinomas but lack of potential as prognostic markers. Asian Pac J Cancer Prev. 15:2145–2152. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Shah P, Gau Y and Sabnis G: Histone deacetylase inhibitor entinostat reverses epithelial to mesenchymal transition of breast cancer cells by reversing the repression of E-cadherin. Breast Cancer Res Treat. 143:99–111. 2014. View Article : Google Scholar

24 

Wang Y, Dong H, Xu M, et al: 37-kDa laminin receptor precursor promotes lung adenocarcinoma cell invasion and metastasis by epithelial-to-mesenchymal transition. Cancer Gene Ther. 21:150–157. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Machado JC, Soares P, Carneiro F, et al: E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas. Lab Invest. 79:459–465. 1999.PubMed/NCBI

26 

Leung WK, Yu J, Ng EK, et al: Concurrent hypermethylation of multiple tumor-related genes in gastric carcinoma and adjacent normal tissues. Cancer. 91:2294–2301. 2001. View Article : Google Scholar : PubMed/NCBI

27 

D’souza B and Taylor-Papadimitriou J: Overexpression of ERBB2 in human mammary epithelial cells signals inhibition of transcription of the E-cadherin gene. Proc Natl Acad Sci USA. 91:7202–7206. 1994.PubMed/NCBI

28 

Dong C, Wu Y, Wang Y, et al: Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene. 32:1351–1362. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Gumireddy K, Li A, Gimotty PA, et al: KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nat Cell Biol. 11:1297–1304. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Muñoz-Nájar UM, Neurath KM, Vumbaca F and Claffey KP: Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene. 25:2379–2392. 2006.PubMed/NCBI

31 

McMahon S, Grondin F, McDonald PP, Richard DE and Dubois CM: Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. J Biol Chem. 280:6561–6569. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Stoeltzing O, McCarty MF, Wey JS, et al: Role of hypoxia-inducible factor 1α in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 96:946–956. 2004.

33 

Kong T, Eltzschig HK, Karhausen J, Colgan SP and Shelley CS: Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of β2 integrin gene expression. Proc Natl Acad Sci USA. 101:10440–10445. 2004.PubMed/NCBI

34 

Higgins DF, Kimura K, Bernhardt WM, et al: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 117:3810–3820. 2007.PubMed/NCBI

35 

Zhou G, Dada LA, Wu M, et al: Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol. 297:L1120–L1130. 2009. View Article : Google Scholar : PubMed/NCBI

36 

Copple BL: Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-β-dependent mechanisms. Liver Int. 30:669–682. 2010.PubMed/NCBI

37 

Leivonen SK and Kähäri VM: Transforming growth factor-β signaling in cancer invasion and metastasis. Int J Cancer. 121:2119–2124. 2007.

38 

Shields MA, Dangi-Garimella S, Krantz SB, Bentrem DJ and Munshi HG: Pancreatic cancer cells respond to type I collagen by inducing snail expression to promote membrane type 1 matrix metalloproteinase-dependent collagen invasion. J Biol Chem. 286:10495–10504. 2011. View Article : Google Scholar

39 

Kang Y and Massagué J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 118:277–279. 2004. View Article : Google Scholar : PubMed/NCBI

40 

Aigner K, Dampier B, Descovich L, et al: The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 26:6979–6988. 2007.

41 

Guaita S, Puig I, Franci C, et al: Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem. 277:39209–39216. 2002. View Article : Google Scholar : PubMed/NCBI

42 

Peinado H and Cano A: A hypoxic twist in metastasis. Nat Cell Biol. 10:253–254. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liu N, Wang Y, Zhou Y, Pang H, Zhou J, Qian P, Liu L and Zhang H: Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition. Oncol Rep 32: 2397-2404, 2014.
APA
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P. ... Zhang, H. (2014). Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition. Oncology Reports, 32, 2397-2404. https://doi.org/10.3892/or.2014.3495
MLA
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P., Liu, L., Zhang, H."Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition". Oncology Reports 32.6 (2014): 2397-2404.
Chicago
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P., Liu, L., Zhang, H."Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition". Oncology Reports 32, no. 6 (2014): 2397-2404. https://doi.org/10.3892/or.2014.3495
Copy and paste a formatted citation
x
Spandidos Publications style
Liu N, Wang Y, Zhou Y, Pang H, Zhou J, Qian P, Liu L and Zhang H: Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition. Oncol Rep 32: 2397-2404, 2014.
APA
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P. ... Zhang, H. (2014). Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition. Oncology Reports, 32, 2397-2404. https://doi.org/10.3892/or.2014.3495
MLA
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P., Liu, L., Zhang, H."Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition". Oncology Reports 32.6 (2014): 2397-2404.
Chicago
Liu, N., Wang, Y., Zhou, Y., Pang, H., Zhou, J., Qian, P., Liu, L., Zhang, H."Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition". Oncology Reports 32, no. 6 (2014): 2397-2404. https://doi.org/10.3892/or.2014.3495
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team