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
April 2012 Volume 40 Issue 4

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
April 2012 Volume 40 Issue 4

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
Article Open Access

Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis

  • Authors:
    • Takaharu Kato
    • Koichi Suzuki
    • Shinichiro Okada
    • Hidenori Kamiyama
    • Takafumi Maeda
    • Masaaki Saito
    • Kei Koizumi
    • Yuichiro Miyaki
    • Fumio Konishi
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan, Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma- cho, Omiya-ku, Saitama, Saitama 330-8503, Japan
    Copyright: © Kato et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 942-950
    |
    Published online on: December 15, 2011
       https://doi.org/10.3892/ijo.2011.1301
  • 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

We previously reported that the Pleckstrin and Sec7 domain-containing (PSD) gene is preferentially methylated in patients with ulcerative colitis (UC) who developed colorectal cancer (CRC), and is implicated in UC-associated carcinogenesis through its inhibition of apoptosis. This study aimed to determine the potential effect of PSD methylation on its downstream molecule, Ras-related C3 botulinum toxin substrate 1 (Rac1), which governs neutrophil chemotaxis and apoptosis signaling. PSD was knocked down in a normal human fibroblast cell line (HNDF) and a neutrophil-like cell line (HL-60). Both NHDF and HL-60 cells exhibited numerous filamentous-actin (F-actin) rich membrane extensions, resulting in the activation of Rac1; this activation was hampered by PSD silencing. Lipopolysaccharide, a reactive oxygen species (ROS) inducer, stimulated NHDF cells to release ROS and activated caspase‑3/7 in the presence of neutrophils, which was inhibited by PSD knockdown. Migration assays demonstrated that chemotaxis of HL-60 cells was affected by PSD silencing in NHDF cells. Tissue sections from 6 UC patients with CRC and 15 UC patients without CRC were examined. To verify Rac1-mediated chemotaxis in tissue sections, we evaluated the grade of neutrophil infiltration by histological assessment and assessed F-actin and PSD expression by immunohistochemistry. Neutrophil infiltration, F-actin and PSD expression were significantly decreased in specimens from UC patients with PSD methylation compared with those without. Decreased levels of F-actin expression were observed in colorectal mucosa, as well as in infiltrating cells with PSD methylation. PSD expression was preferentially inhibited in colorectal mucosa by PSD methylation, whereas PSD expression was rarely observed in infiltrating cells, regardless of PSD methylation status. These data indicate that aberrant methylation of PSD occurs in UC-associated colorectal mucosa, enabling circumvention of Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis, and thus plays a pivotal role in the mechanisms underlying UC-associated carcinogenesis.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Ekbom A, Helmick C, Zack M and Adami HO: Ulcerative colitis and colorectal cancer. a population-based study. N Engl J Med. 323:1228–1233. 1990.

2 

Lashner BA, Silverstein MD and Hanauer SB: Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci. 34:1536–1541. 1989.

3 

Duerr RH, Taylor KD, Brant SR, et al: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 314:1461–1463. 2006.

4 

Franke A, Balschun T, Karlsen TH, et al: Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet. 40:713–715. 2008.

5 

Hugot JP, Chamaillard M, Zouali H, et al: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 411:599–603. 2001.

6 

Barrett JC, Hansoul S, Nicolae DL, et al: Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 40:955–962. 2008.

7 

Hampe J, Franke A, Rosenstiel P, et al: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 39:207–211. 2007.

8 

Rioux JD, Xavier RJ, Taylor KD, et al: Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 39:596–604. 2007.

9 

Barrett JC, Lee JC, Lees CW, et al: Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 41:1330–1334. 2009.

10 

Stoll M, Corneliussen B, Costello CM, et al: Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet. 36:476–480. 2004.

11 

Humbert P, Russell S and Richardson H: Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays. 25:542–553. 2003.

12 

Wakabayashi M, Ito T, Mitsushima M, et al: Interaction of lp-dlg/KIAA0583, a membrane-associated guanylate kinase family protein, with vinexin and beta-catenin at sites of cell-cell contact. J Biol Chem. 278:21709–21714. 2003.

13 

Okada S, Suzuki K, Kato T, et al: Aberrant methylation of the Pleckstrin and Sec7 domain-containing gene is implicated in ulcerative colitis-associated carcinogenesis through its inhibition of apoptosis. Int J Oncol. DOI: 10.3892/ijo.2011.1231. 2011.

14 

Eom YW, Yoo MH, Woo CH, et al: Implication of the small GTPase Rac1 in the apoptosis induced by UV in Rat-2 fibroblasts. Biochem Biophys Res Commun. 285:825–829. 2001.

15 

Gulbins E, Coggeshall KM, Brenner B, Schlottmann K, Linderkamp O and Lang F: Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway. J BiolChem. 271:26389–26394. 1996.

16 

Esteve P, Embade N, Perona R, et al: Rho-regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but Bcl2 dependent pathway. Oncogene. 17:1855–1869. 1998.

17 

Servant G, Weiner OD, Herzmark P, Balla T, Sedat JW and Bourne HR: Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science. 287:1037–1040. 2000.

18 

Servant G, Weiner OD, Neptune ER, Sedat JW and Bourne HR: Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. Mol Biol Cell. 10:1163–1178. 1999.

19 

Wang F, Herzmark P, Weiner OD, Srinivasan S, Servant G and Bourne HR: Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils. Nat Cell Biol. 4:513–518. 2002.

20 

Rutter M, Saunders B, Wilkinson K, et al: Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 126:451–459. 2004.

21 

Franco M, Peters PJ, Boretto J, et al: EFA6, a sec7 domain-containing exchange factor for ARF6, coordinates membrane recycling and actin cytoskeleton organization. EMBO J. 18:1480–1491. 1999.

22 

Kurokawa K, Itoh RE, Yoshizaki H, Nakamura YO and Matsuda M: Coactivation of Rac1 and Cdc42 at lamellipodia and membrane ruffles induced by epidermal growth factor. Mol Biol Cell. 15:1003–1010. 2004.

23 

Boehm JE, Chaika OV and Lewis RE: Rac-dependent anti-apoptotic signaling by the insulin receptor cytoplasmic domain. J BiolChem. 274:28632–28636. 1999.

24 

Joneson T and Bar-Sagi D: Suppression of Ras-induced apoptosis by the RacGTPase. Mol Cell Biol. 19:5892–5901. 1999.

25 

Nishida K, Kaziro Y and Satoh T: Anti-apoptotic function of Rac in hematopoietic cells. Oncogene. 18:407–415. 1999.

26 

Saez R, Chan AM, Miki T and Aaronson SA: Oncogenic activation of human R-ras by point mutations analogous to those of prototype H-ras oncogenes. Oncogene. 9:2977–2982. 1994.

27 

Wang HG, Millan JA, Cox AD, et al: R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism. J Cell Biol. 129:1103–1114. 1995.

28 

Srinivasan S, Wang F, Glavas S, et al: Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol. 160:375–385. 2003.

29 

Lampinen M, Ronnblom A, Amin K, et al: Eosinophil granulocytes are activated during the remission phase of ulcerative colitis. Gut. 54:1714–1720. 2005.

30 

Glogauer M, Marchal CC, Zhu F, et al: Rac1 deletion in mouse neutrophils has selective effects on neutrophil functions. J Immunol. 170:5652–5657. 2003.

31 

Roessner A, Kuester D, Malfertheiner P and Schneider-Stock R: Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract. 204:511–524. 2008.

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kato T, Suzuki K, Okada S, Kamiyama H, Maeda T, Saito M, Koizumi K, Miyaki Y and Konishi F: Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis. Int J Oncol 40: 942-950, 2012.
APA
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M. ... Konishi, F. (2012). Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis. International Journal of Oncology, 40, 942-950. https://doi.org/10.3892/ijo.2011.1301
MLA
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M., Koizumi, K., Miyaki, Y., Konishi, F."Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis". International Journal of Oncology 40.4 (2012): 942-950.
Chicago
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M., Koizumi, K., Miyaki, Y., Konishi, F."Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis". International Journal of Oncology 40, no. 4 (2012): 942-950. https://doi.org/10.3892/ijo.2011.1301
Copy and paste a formatted citation
x
Spandidos Publications style
Kato T, Suzuki K, Okada S, Kamiyama H, Maeda T, Saito M, Koizumi K, Miyaki Y and Konishi F: Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis. Int J Oncol 40: 942-950, 2012.
APA
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M. ... Konishi, F. (2012). Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis. International Journal of Oncology, 40, 942-950. https://doi.org/10.3892/ijo.2011.1301
MLA
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M., Koizumi, K., Miyaki, Y., Konishi, F."Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis". International Journal of Oncology 40.4 (2012): 942-950.
Chicago
Kato, T., Suzuki, K., Okada, S., Kamiyama, H., Maeda, T., Saito, M., Koizumi, K., Miyaki, Y., Konishi, F."Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis". International Journal of Oncology 40, no. 4 (2012): 942-950. https://doi.org/10.3892/ijo.2011.1301
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