Abstract. HOX genes are known not only as master genes that control the morphogenesis, but also as regulator genes that maintain tissue or organ specificity in the adult body. We hypothesized that dysregulated expression of HOX genes was associated with tumor development and malignant progression such as invasion and metastasis. In this study, we analyzed the expression patterns of 39 HOX genes in human invasive ductal breast cancer tissues and normal tissues by the real-time RT-PCR method. We found 11 HOX genes (HOXA1, A2, A3, A5, A9, C11, D3, D4, D8, D9 and D10) expression levels of which were significantly different between cancerous and normal tissues. All 10 genes except HOXC11 were expressed at lower levels in cancerous tissues than normal tissues. Comparing expression levels of each HOX gene among the different types of cancer tissues, the expression level of HOXB7 was lower in lymph node metastasis-positive cancer tissues than negative cancer tissues; those of HOXD12 and D13 were higher in progesterone receptor-positive cancer tissues than negative cancer tissues; and the expression level of HOXC5 was lower in cancerous tissues with mutated-type p53 than in normal and cancerous tissues with wild-type p53. These results suggest that the aberrant expression of HOX genes is related to the development of breast cancer and malignant behavior of cancer cells.

Relatively little is known about how recirculation of lymphocytes through the inflamed intestinal mucosa is regulated. The aim of this study was to investigate the dynamic process of T lymphocyte-endothelial cell adhesion in TNF-alpha-challenged murine colonic mucosa by intravital microscopy. T lymphocytes from spleen (SPL) and intestinal lamina propria (LPL) were fluorescence labeled, and their adhesion to microvessels in the colonic mucosa was observed. In TNF-alpha (25 microg/kg)-stimulated colonic venules, an enhanced adhesion of SPL and LPL was demonstrated, with dominant recruitment of LPLs. The magnitude of the increased LPL adhesion was more significant in the colon than in the small intestine. These T lymphocyte interactions in the colonic mucosa were significantly reduced by blocking MAbs against either mucosal addressin cell adhesion molecule-1 (MAdCAM-1), VCAM-1, alpha(4)-integrin, or beta(7)-integrin but not by anti-ICAM-1. Immunohistochemistry revealed significant MAdCAM-1 expression in the lamina propria and VCAM-1 expression in the submucosa of TNF-alpha-treated colon. Spatial heterogeneity of MAdCAM-1 and VCAM-1 activation following TNF-alpha challenge may promote specific T lymphocyte recruitment in the inflamed colonic mucosa.

SummaryAlthough enhanced lymphocyte trafficking is associated with colitis formation, little information about its regulation is available. The aim of this study was to examine how the murine liver and activation-regulated chemokine (mLARC/CCL20) contributes to lymphocyte recruitment in concert with vascular adhesion molecules in murine chronic experimental colitis. T and B lymphocytes isolated from the spleen were fluorescence-labelled and administered to recipient mice. Lymphocyte adhesion to microvessels of the colonic mucosa and submucosa was observed with an intravital microscope. To induce colitis, the mice received two cycles of treatment with 2% dextran sodium sulphate (DSS). In some of the experiments antibodies against the adhesion molecules or anti-mLARC/CCL20 were administered, or CC chemokine receptor 6 (CCR6) of the lymphocytes was desensitized with excess amounts of mLARC/CCL20. Significant increases in T and B cell adhesion to the microvessels of the DSS-treated mucosa and submucosa were observed. In chronic colitis, the accumulation of lymphocytes was significantly inhibited by anti-mucosal addressin cell adhesion molecule (MAdCAM)-1 mAb, but not by anti-vascular cell adhesion molecule-1. In DSS-treated colonic tissue, the expression of mLARC/CCL20 was significantly increased, the blocking of mLARC/CCL20 by monoclonal antibody or the desensitization of CCR6 with mLARC/CCL20 significantly attenuated the DSS-induced T and B cell accumulation. However, the combination of blocking CCR6 with MAdCAM-1 did not further inhibit these accumulations. These results suggest that in chronic DSS-induced colitis, both MAdCAM-1 and mLARC/CCL20 may play important roles in T and B lymphocyte adhesion in the inflamed colon under flow conditions.

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. Chronic allergy to dietary ovalbumin induces lymphocyte migration to rat small intestinal mucosa that is inhibited by MAdCAM-1. Am J Physiol Gastrointest Liver Physiol 286: G702-G710, 2004. First published December 11, 2003 10.1152/ajpgi.00183.2003.-Few models have described a chronic food allergy with morphological changes in the intestinal mucosa. Here we established an ovalbumin (OVA)-induced, cell-mediated, allergic rat model and examined lymphocyte migration in the gut. Brown Norway rats were intraperitoneally sensitized to OVA and then given 10 mg OVA/day by gastric intubation for 6 wk. Lymphocyte subsets and adhesion molecules were examined immunohistochemically, and the migration of T lymphocytes to microvessels of Peyer's patches and villus mucosa was observed by using an intravital microscope. Serum OVA-specific IgG and IgE levels were increased in animals repeatedly exposed to OVA. Significant villus atrophy and increased crypt depth was accompanied by increased infiltration of T lymphocytes in the small intestinal mucosa of the group given OVA. Expression of rat mast cell protease II and of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) was also increased in these groups. The administration of anti-MAdCAM-1 antibody significantly attenuated the OVA-induced changes in the mucosal architecture and in CD4 T lymphocyte infiltration. Intravital observation demonstrated that in rats with a chronic allergy, T lymphocytes significantly accumulated in villus microvessels as well as in Peyer's patches via a MAdCAM-1-dependent process. Our model of chronic food allergy revealed that lymphocyte migration was increased with MAdCAM-1 upregulation.Brown Norway rats; rat mast cell protease II; delayed type hypersensitivity; Peyer's patch; intercellular adhesion molecule-1 THE CLINICAL MANIFESTATIONS of allergic reactions from food intolerance may be localized to the gut, including abdominal discomfort, nausea, vomiting, and diarrhea. Type I or IgEmediated allergic reactions are involved in early-phase symptoms of food allergy (6,8). On the other hand, cell-mediated reactions are also involved in the late phase and symptoms are often prolonged, causing mucosal damage such as crypt hyperplasia, villus atrophy, and lymphocyte infiltration (11,13,27,30). Because human research is restricted, animal models of food allergies would be of significant value. Several efforts have been made to develop rodent models of food allergy (10,14,32). However, few models have been validated for studying the effects of chronic antigen exposure or for relevance to clinical situations involving both IgE-and cell-mediated reactions (21,22,28). Although several groups (10) have investigated the effect of repeated oral challenge in rats with IgEmediated hypersensitivity, lymphocyte infiltration was not obvious in the intestinal mucosa of these animals. Only a recent report by Yang et al. (36) has demonstrated that the oral antigen challenge of sensitized Sprague-Dawley rats induces sustained epithelial dysfunction with inflammator...