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Transgenic Research

, Volume 14, Issue 5, pp 655–663 | Cite as

Gastric Pit Cell Hyperplasia and Glandular Atrophy in Carbonic Anhydrase IX Knockout Mice: Studies on Two Strains C57/BL6 and BALB/C

  • Mari LeppilampiEmail author
  • Tuomo J. Karttunen
  • Jyrki Kivelä
  • Marta Ortova Gut
  • Silvia Pastoreková
  • Jaromir Pastorek
  • Seppo Parkkila
Article

Abstract

Carbonic anhydrase (CA) isoenzyme IX is a hypoxia-inducible enzyme, which is expressed in the human and rodent gastrointestinal tract and overexpressed in several different tumors. Functionally, it has probably an effect on proliferation and differentiation of gastrointestinal epithelial cells. It may also participate in gastric morphogenesis, since a recent study has shown gastric pit cell hyperplasia and glandular atrophy in CA IX-knockout mice. However, it is not known whether CA IX produces morphological changes in the gastric mucosa, which can turn into a dysplasia or malignancy in the presence of some carcinogenic factors. High-salt diet is considered such a factor which has been shown to modulate Helicobacter pylori-associated carcinogenesis. We produced two strains of CA IX-knockout mice, C57/BL6 and BALB/c, and the mice ate either standard or high-salt feed for 20 weeks. Stomach samples were collected from 40 Car9/ knockout mice and 37 wildtype littermates, and the tissue sections were examined for histology. CA IX-deficiency caused gastric pit cell hyperplasia and glandular atrophy in both BALB/c and C57/BL6 strains. Excess dietary salt had no significant effect on the severity of pit cell hyperplasia. No dysplasia was found in any of the groups. In C57/BL6 mice, CA IX-deficiency was associated with gastric submucosal inflammation. The results indicate that CA IX-deficiency provides a useful model to study the mechanisms of gastric morphogenesis and epithelial integrity. Further studies are needed to see whether CA IX has a role in the regulation of immune response. The findings suggest that although CA IX-deficiency is not a tumor-promoting factor per se, it induces glandular atrophy in the body mucosa, a lesion which is considered to be a preneoplastic alteration in the stomach.

Keywords

atrophy carbonic anhydrase hyperplasia knockout stomach 

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References

  1. Anderson, MS, Venanzi, ES, Klein, L, Chen, Z, Berzins, SP,  et al. 2002Projection of an immunological self shadow within the thymus by the aire proteinScience29813951401CrossRefPubMedGoogle Scholar
  2. Bartosova, M, Parkkila, S, Pohlodek, K, Karttunen, TJ, Galbavy, S,  et al. 2002Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2J Pathol197314321CrossRefPubMedGoogle Scholar
  3. Brizel, DM, Scully, SP, Harrelson, JM, Layfield, LJ, Bean, JM,  et al. 1996Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcomaCancer Res56941943PubMedGoogle Scholar
  4. Chia, SK, Wykoff, CC, Watson, PH, Han, C, Leek, RD,  et al. 2001Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinomaJ Clin Oncol1936603668PubMedGoogle Scholar
  5. Correa, P, Piazuelo, MB, Camargo, MC 2004The future of gastric cancer preventionGastric Cancer7916CrossRefPubMedGoogle Scholar
  6. Fox, JG, Dangler, CA, Taylor, NS, King, A, Koh, TJ,  et al. 1999High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 miceCancer Res5948234828PubMedGoogle Scholar
  7. Giatromanolaki, A, Koukourakis, MI, Sivridis, E, Pastorek, J, Wykoff, CC,  et al. 2001Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancerCancer Res6179927998PubMedGoogle Scholar
  8. Hewett-Emmett D (2000) Evolution and distribution of the carbonic anhydrase gene families. Exs : 29–76.Google Scholar
  9. Hewett-Emmett, D, Tashian, RE 1996Functional diversity, conservation, and convergence in the evolution of the alpha-, beta-, and gamma-carbonic anhydrase gene familiesMol Phylogenet Evol55077CrossRefPubMedGoogle Scholar
  10. Hilvo, M, Rafajova, M, Pastorekova, S, Pastorek, J, Parkkila, S 2004Expression of carbonic anhydrase IX in mouse tissuesJ Histochem Cytochem5213131322CrossRefPubMedGoogle Scholar
  11. Hockel, M, Schlenger, K, Aral, B, Mitze, M, Schaffer, U,  et al. 1996Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervixCancer Res5645094515PubMedGoogle Scholar
  12. Joossens, JV, Hill, MJ, Elliott, P, Stamler, R, Lesaffre, E,  et al. 1996Dietary salt, nitrate and stomach cancer mortality in 24 countries. European Cancer Prevention (ECP) and the INTERSALT Cooperative Research GroupInt J Epidemiol25494504PubMedGoogle Scholar
  13. Kivela, AJ, Parkkila, S, Saarnio, J, Karttunen, TJ, Kivela, J,  et al. 2000Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumoursHistochem Cell Biol114197204PubMedGoogle Scholar
  14. Lee, SA, Kang, D, Shim, KN, Choe, JW, Hong, WS,  et al. 2003Effect of diet and Helicobacter pylori infection to the risk of early gastric cancerJ Epidemiol13162168PubMedGoogle Scholar
  15. Lehtonen, J, Shen, B, Vihinen, M, Casini, A, Scozzafava, A,  et al. 2004Characterization of CA XIII, a novel member of the carbonic anhydrase isozyme familyJ Biol Chem27927192727CrossRefPubMedGoogle Scholar
  16. Leppilampi, M, Saarnio, J, Karttunen, TJ, Kivela, J, Pastorekova, S,  et al. 2003Carbonic anhydrase isozymes IX and XII in gastric tumorsWorld J Gastroenterol913981403PubMedGoogle Scholar
  17. Liao, SY, Brewer, C, Zavada, J, Pastorek, J, Pastorekova, S,  et al. 1994Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomasAm J Pathol145598609PubMedGoogle Scholar
  18. Liao, SY, Aurelio, ON, Jan, K, Zavada, J, Stanbridge, EJ 1997Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidneyCancer Res5728272831PubMedGoogle Scholar
  19. Maseide, K, Kandel, RA, Bell, RS, Catton, CN, O’Sullivan, B,  et al. 2004Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcomaClin Cancer Res1044644471CrossRefPubMedGoogle Scholar
  20. McKiernan, JM, Buttyan, R, Bander, NH, Stifelman, MD, Katz, AE,  et al. 1997Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinomaCancer Res5723622365PubMedGoogle Scholar
  21. Mohammadi, M, Czinn, S, Redline, R, Nedrud, J 1996Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitivity response in the stomachs of miceJ Immunol15647294738PubMedGoogle Scholar
  22. Opavsky, R, Pastorekova, S, Zelnik, V, Gibadulinova, A, Stanbridge, EJ,  et al. 1996Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationshipsGenomics33480487CrossRefPubMedGoogle Scholar
  23. Ortova Gut, MO, Parkkila, S, Vernerova, Z, Rohde, E, Zavada, J,  et al. 2002Gastric hyperplasia in mice with targeted disruption of the carbonic anhydrase gene Car9Gastroenterology12318891903CrossRefPubMedGoogle Scholar
  24. Parkkila, S 2000An overview of the distribution and function of carbonic anhydrase in mammalsExs907993PubMedGoogle Scholar
  25. Parkkila, S, Parkkila, AK 1996Carbonic anhydrase in the alimentary tract. Roles of the different isozymes and salivary factors in the maintenance of optimal conditions in the gastrointestinal canalScand J Gastroenterol31305317PubMedGoogle Scholar
  26. Pastorek, J, Pastorekova, S, Callebaut, I, Mornon, JP, Zelnik, V,  et al. 1994Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segmentOncogene928772888PubMedGoogle Scholar
  27. Pastorekova, S, Parkkila, S, Parkkila, AK, Opavsky, R, Zelnik, V,  et al. 1997Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tractsGastroenterology112398408CrossRefPubMedGoogle Scholar
  28. Pastorekova, S, Zavadova, Z, Kostal, M, Babusikova, O, Zavada, J 1992A novel quasi-viral agent, MaTu, is a two-component systemVirology187620626CrossRefPubMedGoogle Scholar
  29. Potter, CP, Harris, AL 2003Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancerBr J Cancer8927CrossRefPubMedGoogle Scholar
  30. Saarnio, J, Parkkila, S, Parkkila, AK, Pastorekova, S, Haukipuro, K,  et al. 2001Transmembrane carbonic anhydrase, MN/CA IX, is a potential biomarker for biliary tumoursJ Hepatol35643649CrossRefPubMedGoogle Scholar
  31. Saarnio, J, Parkkila, S, Parkkila, AK, Haukipuro, K, Pastorekova, S,  et al. 1998aImmunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferationAm J Pathol153279285Google Scholar
  32. Saarnio, J, Parkkila, S, Parkkila, AK, Waheed, A, Casey, MC,  et al. 1998bImmunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in the epithelial cells with the highest proliferative capacityJ Histochem Cytochem46497504Google Scholar
  33. Sly, WS, Hu, PY 1995Human carbonic anhydrases and carbonic anhydrase deficienciesAnnu Rev Biochem64375401CrossRefPubMedGoogle Scholar
  34. Smythies, LE, Waites, KB, Lindsey, JR, Harris, PR, Ghiara, P,  et al. 2000Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient miceJ Immunol16510221029PubMedGoogle Scholar
  35. Stewart, M, Talks, K, Leek, R, Turley, H, Pezzella, F,  et al. 2002Expression of angiogenic factors and hypoxia inducible factors HIF 1, HIF 2 and CA IX in non-Hodgkin’s lymphomaHistopathology40253260CrossRefPubMedGoogle Scholar
  36. Supuran, CT, Briganti, F, Tilli, S, Chegwidden, WR, Scozzafava, A 2001Carbonic anhydrase inhibitors: sulfonamides as antitumor agents?Bioorg Med Chem9703714CrossRefPubMedGoogle Scholar
  37. Tominaga, K, Matsuda, J, Kido, M, Naito, E, Yokota, I,  et al. 2004Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the “twitcher” mouse model of globoid cell leukodystrophyJ Neurosci Res77507516CrossRefPubMedGoogle Scholar
  38. Tuyns, AJ 1988Salt and gastrointestinal cancerNutr Cancer11229232PubMedGoogle Scholar
  39. Vermylen, P, Roufosse, C, Burny, A, Verhest, A, Bosschaerts, T,  et al. 1999Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinomaEur Respir J14806811CrossRefPubMedGoogle Scholar
  40. Wykoff, CC, Beasley, NJ, Watson, PH, Turner, KJ, Pastorek, J,  et al. 2000Hypoxia-inducible expression of tumor-associated carbonic anhydrasesCancer Res6070757083PubMedGoogle Scholar
  41. Zavada, J, Zavadova, Z, Pastorekova, S, Ciampor, F, Pastorek, J,  et al. 1993Expression of MaTu-MN protein in human tumor cultures and in clinical specimensInt J Cancer54268274PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Mari Leppilampi
    • 1
    Email author
  • Tuomo J. Karttunen
    • 2
  • Jyrki Kivelä
    • 3
    • 4
  • Marta Ortova Gut
    • 5
  • Silvia Pastoreková
    • 6
  • Jaromir Pastorek
    • 6
  • Seppo Parkkila
    • 1
    • 7
  1. 1.Department of Clinical ChemistryUniversity of OuluOuluFinland
  2. 2.Department of PathologyUniversity of OuluOuluFinland
  3. 3.Institute of DentistryUniversity of HelsinkiHelsinkiFinland
  4. 4.Research Institute of Military MedicineCentral Military HospitalHelsinkiFinland
  5. 5.Department of Molecular GeneticsInstitute of Molecular Pharmacology and Medical Center of Free University of BerlinGermany
  6. 6.Centre of Molecular Medicine, Institute of VirologySlovak Academy of SciencesBratislavaSlovak Republic
  7. 7.Institute of Medical TechnologyUniversity of Tampere and Tampere University HospitalTampereFinland

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