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    CXCL12 expression in murine stomach regions, & lack of correlation between its expression and <em>H.felis</em>-induced gastritis and gastric carcinoma

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    Authors
    Tadros, Thomas
    Faculty Advisor
    Takaishi, Shigeo; Houghton, Jean Marie; Stoicov, Calin; Barnard, Graham
    UMass Chan Affiliations
    Department of Medicine, Division of Gastroenterology
    Document Type
    Abstract
    Publication Date
    2004-06-01
    Keywords
    Chemokines, CXC
    Helicobacter felis
    Stomach
    Mice
    Gastritis
    Stomach Neoplasms
    Receptors, CXCR4
    Cancer Biology
    Digestive System Diseases
    Gastroenterology
    Oncology
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    Abstract
    CXCL12 is a chemokine with diverse functions including: induction of chemotaxis and activation of leukocytes in response to pro-inflammatory mediators; murine B-cell lymphopoiesis, bone marrow myelopoiesis, & embryonic formation of the ventricular septum (Nagasawa et al., 1996); inhibition of HIV infection of T-cells (Oberlin et al., 1996); cell adhesion and migration (Peled et al., 2002; Gotoh et al., 1999). It has been shown that there is reduced expression of CXCL12 in many cancers, including hepato-cellular-, colon-, and esophageal cancers (Begum et al., 1996). However, in gastric cancer, both increased and decreased expression have been demonstrated (Shibuta et al., 1997). It is not known whether CXCL12 expression varies among the different regions of the stomach. H.felis infects the fundus and induces gastric carcinoma close to the gastroesophageal junction in mice. In humans, H.pylori infects the antrum and induces carcinoma in the non-cardia region of the stomach. Thus, regional variation in CXCL12 expression may exist in relation to these pathologies. The purpose of this experiment is: (1) to determine whether variation in expression of CXCL12 and its receptor CXCR4 exists in different regions of murine stomach; and (2) to determine whether expression of CXCL12 and CXCR4 changes during pathogenesis of H.felis-induced murine gastritis and gastric carcinoma. The hypothesis is that: (1) in normal mouse stomach, there will be no regional variation in expression of CXCL12 or CXCR4; and (2) in the inflammatory stage of H.felis infection, there will be increased expression of CXCL12 and CXCR4, while in the neoplastic and malignant stages there will be reduced expression. To test the hypothess, mice were infected orally with H.felisto induce gastritis and gastric cancer. The stomachs of these mice and normal mice were procured. RNA was isolated from different regions of the stomach and reverse-transcribed to cDNA by oligo-dT priming. cDNA was amplified by real-time PCR using primers for CXCL12, CXCR4, and a control gene G3PDH. It was found that: (1) in mouse stomach, there is significantly greater expression of CXCL12 mRNA in the fundus (5.3 times greater) and lesser curvature (3.4 times greater) compared to the antrum; (2) there is a tendency towards increased expression of CXCL12 mRNA during the inflammatory phase with a subsequent reduced expression in the neoplastic phase; and (3) there is a tendency towards increased expression of the receptor CXCR4 mRNA in both inflammatory and neoplastic phases. Since changes in expression of CXCL12 and its receptor were not statistically-significant, increasing the number of gastritis and gastric cancer samples would help validate the results. Further, micro-dissection of stomach tissue using laser capture to separate cancer cells from stromal cells could more clearly demonstrate differences in CXCL12 and CXCR4 expression seen. REFERENCES 1) Baggiolini M Dewald B Moser B et al. Adv. Immunol., 55, 97-179 (1994).* 2) Barnard GF Staniunas RJ Mori M et al. Gastric and hepatocellular carcinomas do not overexpress the same ribosomal protein messenger RNAs as colonic carcinoma. Cancer Research, 53, 4048-4052 (1993). 3) Begum NA Coker A Shibuta K et al. Loss of hIRH mRNA expression from premalignant adenomas and malignant cell lines. Biochemical and biophysical research communications, 229, 864-868 (1996). 4) Bernard PS Wittwer CT. Real-time PCR technology for cancer diagnostics. Clinical Chemistry, 48:8, 1178-1185 (2002). 5) Gotoh A Reid S Miyazawa K et al. SDF-1 suppresses cytokine-induced adhesion of human haemopoietic progenitor cells to immobilized fibronectin. British Journal of Haematology, 106(1), 171-174 (1999). 6) Klein D. Quantification using real-time PCR technology: applications and limitations. TRENDS in Molecular Medicine, 8:6, 257-260 (2002). 7) Lehmann U Kreipe H. Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. Methods, 25, 409-418 (2001). 8) Nagasawa T Hirota S Tachibana K et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature, 382, 635-638 (1996). 9) Nagasawa S Kikutani H Kishimoto T et al. Proc. Natl. Acad. Sci. USA, 91, 2305-2309 (1994).* 10) Oberlin E et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature (London), 382, 833-835 (1996).* 11) Oppenheim J Zachariae C Mukaida N et al. Ann. Rev. Immunol., 9, 617-648 (1991).* 12) Peled A Hardan I Trakhtenbrot L et al. Immature leukemic CD34+CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1. Stem Cells, 20(3), 259-266 (2002). 13) Shibuta K Begum NA Mori M et al. Reduced expression of the CXC chemokine hIRH/SDF-1alpha mRNA in hepatoma and digestive tract cancer. International Journal of Cancer, 73, 656-662 (1997). 14) Shirozu M Nakano T Inazawa J et al. Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics, 28, 495-500 (1995). 15) Smith DR Polverini PJ Kunkel SL et al. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J. exp. Med., 179, 1409-1415 (1994).* 16) Tashiro K Tada H Heilker R et al. Science, 261, 600-603 (1993).* 17) Von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res., 14, 4683-4690 (1986).* 18) Wang T Dangler C Chen D et al. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology, 118(1), 36-47 (2000).
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49380
    Notes

    The author participated in this study as a medical student in the Senior Scholars research program at the University of Massachusetts Medical School.

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