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
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
2014-January Volume 44 Issue 1

Full Size Image

Cover Legend PDF

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
2014-January Volume 44 Issue 1

Full Size Image

Cover Legend PDF

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

Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma

  • Authors:
    • Mitsuro Kanda
    • Shuji Nomoto
    • Hisaharu Oya
    • Hideki Takami
    • Soki Hibino
    • Mitsuhiro Hishida
    • Masaya Suenaga
    • Suguru Yamada
    • Yoshikuni Inokawa
    • Yoko Nishikawa
    • Mikako Asai
    • Tsutomu Fujii
    • Hiroyuki Sugimoto
    • Yasuhiro Kodera
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan
  • Pages: 44-52
    |
    Published online on: November 5, 2013
       https://doi.org/10.3892/ijo.2013.2165
  • 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

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and its prognosis is poor. Novel targets for treating recurrence and progression along with associated biomarkers are urgently required. In this study, the expression and regulatory mechanism of DENN/MADD domain containing 2D (DENND2D) were investigated in an attempt to identify a tumor suppressor gene for HCC regulated by silencing through promoter hypermethylation. The levels of DENND2D expression in HCC cell lines and surgical specimens were determined using a quantitative polymerase chain reaction assay and the relationship between the expression levels of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanisms of DENND2D expression in HCC. Most HCC cell lines (89%) and surgical specimens (78%) expressed lower levels of DENND2D mRNA compared with normal liver tissue. In contrast, there was no significant difference in the expression levels of DENND2D mRNA between normal tissues of HCC patients with and without cirrhosis. The expression patterns of DENND2D protein and mRNA were consistent. Patients with significantly lower levels of DENND2D mRNA in HCC tissues had remarkably earlier recurrences after hepatectomy and their prognosis worsened. The DENND2D promoter was methylated in eight out of nine HCC cell lines and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in HCC tissues (75%) and was significantly associated with downregulation of DENND2D mRNA expression. DENND2D is a candidate tumor suppressor gene that is inactivated by promoter hypermethylation in patients with HCC and may serve as a novel biomarker of early recurrence of HCC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1. 

Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI

2. 

Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar

3. 

Della C and Colombo M: Surveillance for hepatocellular carcinoma. Semin Oncol. 39:384–398. 2012. View Article : Google Scholar

4. 

Yang JD and Roberts LR: Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 7:448–458. 2010. View Article : Google Scholar : PubMed/NCBI

5. 

Yu MC and Yuan JM: Environmental factors and risk for hepatocellular carcinoma. Gastroenterology. 127:72–78. 2004. View Article : Google Scholar

6. 

Ponder BA: Cancer genetics. Nature. 411:336–341. 2001. View Article : Google Scholar : PubMed/NCBI

7. 

Cheng YY, Jin H, Liu X, Siu JM, Wong YP, Ng EK, Yu J, Leung WK, Sung JJ and Chan FK: Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer. Br J Cancer. 99:2083–2087. 2008. View Article : Google Scholar : PubMed/NCBI

8. 

Esteller M: Epigenetics in cancer. N Engl J Med. 358:1148–1159. 2008. View Article : Google Scholar

9. 

Kanda M, Nomoto S, Okamura Y, Hayashi M, Hishida M, Fujii T, Nishikawa Y, Sugimoto H, Takeda S and Nakao A: Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma. Mol Carcinog. 50:571–579. 2011. View Article : Google Scholar : PubMed/NCBI

10. 

Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S and Nakao A: Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol. 35:477–483. 2009.

11. 

Kanda M, Nomoto S, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S and Nakao A: Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J Surg Oncol. 98:190–196. 2008. View Article : Google Scholar : PubMed/NCBI

12. 

Stenmark H: Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 10:513–525. 2009. View Article : Google Scholar : PubMed/NCBI

13. 

Pawson T and Nash P: Assembly of cell regulatory systems through protein interaction domains. Science. 300:445–452. 2003. View Article : Google Scholar : PubMed/NCBI

14. 

Marat AL and McPherson PS: The connecdenn family, Rab35 guanine nucleotide exchange factors interfacing with the clathrin machinery. J Biol Chem. 285:10627–10637. 2010. View Article : Google Scholar : PubMed/NCBI

15. 

Sa=to M, Sato K, Liou W, Pant S, Harada A and Grant BD: Regulation of endocytic recycling by C. elegans Rab35 and its regulator RME-4, a coated-pit protein. EMBO J. 27:1183–1196. 2008.PubMed/NCBI

16. 

Levivier E, Goud B, Souchet M, Calmels TP, Mornon JP and Callebaut I: uDENN, DENN, and dDENN: indissociable domains in Rab and MAP kinases signaling pathways. Biochem Biophys Res Commun. 287:688–695. 2001. View Article : Google Scholar : PubMed/NCBI

17. 

Allaire PD, Marat AL, Dall’Armi C, Di Paolo G, McPherson PS and Ritter B: The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes. Mol Cell. 37:370–382. 2010. View Article : Google Scholar : PubMed/NCBI

18. 

Knödler A, Feng S, Zhang J, Zhang X, Das A, Peränen J and Guo W: Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci USA. 107:6346–6351. 2010.PubMed/NCBI

19. 

Denef N, Chen Y, Weeks SD, Barcelo G and Schüpbach T: Crag regulates epithelial architecture and polarized deposition of basement membrane proteins in Drosophila. Dev Cell. 14:354–364. 2008. View Article : Google Scholar : PubMed/NCBI

20. 

Rink J, Ghigo E, Kalaidzidis Y and Zerial M: Rab conversion as a mechanism of progression from early to late endosomes. Cell. 122:735–749. 2005. View Article : Google Scholar : PubMed/NCBI

21. 

Girard M, Allaire PD, McPherson PS and Blondeau F: Non-stoichiometric relationship between clathrin heavy and light chains revealed by quantitative comparative proteomics of clathrin-coated vesicles from brain and liver. Mol Cell Proteomics. 4:1145–1154. 2005. View Article : Google Scholar

22. 

Majidi M, Hubbs AE and Lichy JH: Activation of extracellular signal-regulated kinase 2 by a novel Abl-binding protein, ST5. J Biol Chem. 273:16608–16614. 1998. View Article : Google Scholar : PubMed/NCBI

23. 

Marat AL, Dokainish H and McPherson PS: DENN domain proteins: regulators of Rab GTPases. J Biol Chem. 286:13791–13800. 2011. View Article : Google Scholar : PubMed/NCBI

24. 

Postel EH, Weiss VH, Beneken J and Kirtane A: Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. Proc Natl Acad Sci USA. 93:6892–6897. 1996. View Article : Google Scholar : PubMed/NCBI

25. 

Ling B, Zheng H, Fu G, Yuan J, Shi T, Chen S, Liu Y, Liu Y, Cao Y, Zheng S, Guo S, Han N, Gao Y, Cheng S and Zhang K: Suppression of non-small cell lung cancer proliferation and tumorigenicity by DENND2D. Lung Cancer. 79:104–110. 2013. View Article : Google Scholar : PubMed/NCBI

26. 

International Union Against Cancer: TNM Classification of Malignant Tumors. 7th edition. Wiley-Blackwell; New York, NY: 2009

27. 

Takai D and Jones PA: Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci USA. 99:3740–3745. 2002. View Article : Google Scholar : PubMed/NCBI

28. 

Takai D and Jones PA: The CpG island searcher: a new WWW resource. In Silico Biol. 3:235–240. 2003.PubMed/NCBI

29. 

Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR and Berry DP: Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer. 43:979–992. 2007. View Article : Google Scholar : PubMed/NCBI

30. 

Herath NI, Leggett BA and MacDonald GA: Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol. 21:15–21. 2006. View Article : Google Scholar : PubMed/NCBI

31. 

Tischoff I and Tannapfe A: DNA methylation in hepatocellular carcinoma. World J Gastroenterol. 14:1741–1748. 2008. View Article : Google Scholar : PubMed/NCBI

32. 

Bloethner S, Mould A, Stark M and Hayward NK: Identification of ARHGEF17, DENND2D, FGFR3, and RB1 mutations in melanoma by inhibition of nonsense-mediated mRNA decay. Genes Chromosomes Cancer. 47:1076–1085. 2008. View Article : Google Scholar : PubMed/NCBI

33. 

Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ and Barr FA: Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. J Cell Biol. 191:367–381. 2010. View Article : Google Scholar : PubMed/NCBI

34. 

Carroll KS, Hanna J, Simon I, Krise J, Barbero P and Pfeffer SR: Role of Rab9 GTPase in facilitating receptor recruitment by TIP47. Science. 292:1373–1376. 2001. View Article : Google Scholar : PubMed/NCBI

35. 

Kloer DP, Rojas R, Ivan V, Moriyama K, van Vlijmen T, Murthy N, Ghirlando R, van der Sluijs P, Hurley JH and Bonifacino JS: Assembly of the biogenesis of lysosome-related organelles complex-3 (BLOC-3) and its interaction with Rab9. J Biol Chem. 285:7794–7804. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Hishida M, Suenaga M, Yamada S, Inokawa Y, Nishikawa Y, Nishikawa Y, et al: Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. Int J Oncol 44: 44-52, 2014.
APA
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M. ... Kodera, Y. (2014). Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. International Journal of Oncology, 44, 44-52. https://doi.org/10.3892/ijo.2013.2165
MLA
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M., Suenaga, M., Yamada, S., Inokawa, Y., Nishikawa, Y., Asai, M., Fujii, T., Sugimoto, H., Kodera, Y."Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma". International Journal of Oncology 44.1 (2014): 44-52.
Chicago
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M., Suenaga, M., Yamada, S., Inokawa, Y., Nishikawa, Y., Asai, M., Fujii, T., Sugimoto, H., Kodera, Y."Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma". International Journal of Oncology 44, no. 1 (2014): 44-52. https://doi.org/10.3892/ijo.2013.2165
Copy and paste a formatted citation
x
Spandidos Publications style
Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Hishida M, Suenaga M, Yamada S, Inokawa Y, Nishikawa Y, Nishikawa Y, et al: Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. Int J Oncol 44: 44-52, 2014.
APA
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M. ... Kodera, Y. (2014). Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. International Journal of Oncology, 44, 44-52. https://doi.org/10.3892/ijo.2013.2165
MLA
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M., Suenaga, M., Yamada, S., Inokawa, Y., Nishikawa, Y., Asai, M., Fujii, T., Sugimoto, H., Kodera, Y."Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma". International Journal of Oncology 44.1 (2014): 44-52.
Chicago
Kanda, M., Nomoto, S., Oya, H., Takami, H., Hibino, S., Hishida, M., Suenaga, M., Yamada, S., Inokawa, Y., Nishikawa, Y., Asai, M., Fujii, T., Sugimoto, H., Kodera, Y."Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma". International Journal of Oncology 44, no. 1 (2014): 44-52. https://doi.org/10.3892/ijo.2013.2165
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