APO-1 is a 48-kDa cell-membrane protein identical to the Fas antigen now designated CD95. It is a member of the NGF/TNF receptor superfamily. Anti-APO-1 monoclonal antibody induces apoptosis in a variety of cell types expressing this antigen. We immunohistochemically investigated APO-1 expression in normal colon mucosa, 20 adenomas, 258 colon carcinomas and 10 liver metastases and carried out in vitro studies using a panel of colon-carcinoma cell lines. Immunohistochemically, APO-1 was regularly expressed at the basolateral membrane of normal colon epithelia. In a minor fraction of colon adenomas and in 39.1% of colon carcinomas APO-1 expression was diminished and in 48.1% of carcinomas, predominantly of the non-mucinous type, APO-1 expression was completely abrogated. The normal level of APO-1 in carcinomas was correlated with the mucinous type. Reduced/lost APO-1 expression was more frequent in rectal carcinomas. Complete loss of APO-1 was more frequent in tumors that had already metastasized. APO-1 expression in liver metastases essentially corresponded to that of the primary tumors. Comparative analysis with data from previous studies revealed that the mode of APO-1 expression is correlated with that of HLA-A,B,C./beta 2m, HLA-DR, HLA-D-associated invariant chain and of the secretory component. Surface expression of APO-1 was heterogeneous in colon-carcinoma cell lines; SW480 expressed considerable amounts of APO-1 on all cells, while HT-29 constitutively did less so and only in a minority of cells. Surface density of APO-1 and the fraction of positive cells in HT-29 was enhanced by interferon-gamma (IFN-gamma) and, additively, by tumor necrosis factor-alpha (TNF-alpha), whereas in SW480 APO-1 expression was not modulated by these cytokines. We conclude that neoplastic transformation of colon epithelium often leads to a loss of the physiologic, high level of surface APO-1 by giving rise either to a stable lack of APO-1 or to an IFN-gamma/TNF-alpha-sensitive phenotype of inducible APO-1 expression.
IntroductionFOXO1 belongs to the subgroup O of forkhead transcription factors (FOX), which share the highly conserved forkhead DNAbinding domain. This O subgroup consists of the 4 members, FOXO1, FOXO3, FOXO4, and FOXO6. 1 FOXO transcription factors control different cellular processes, such as stress response, proliferation, apoptosis, and cell differentiation. 2 FOXO target genes include the cell-cycle regulators CDKN1A and CDKN1B, proapoptotic genes BIM, PMAIP1/NOXA, and FASL as well as oxidative stress protectors SOD2 and CAT. 1,3,4 FOXO1 is of particular interest in B cells because it is highly expressed (http://biogps.gnf.org) and plays a nonredundant role in B-cell differentiation by activating recombination activating genes Rag1 and Rag2 and germinal center (GC) genes Bcl6 and Aicda. [5][6][7] In addition, FOXO1 was reported to be a regulator of B-cell death, and its inactivation by B-cell receptor signaling to AKT/PKB kinase was found to be critical for survival of mature B cells. 8 Several other kinases, including the IB kinase 9 and ERK, 10 have been identified to phosphorylate and facilitate nuclear export of FOXO proteins.It is well documented that the oncogenic program of B-cell lymphomas (BCLs) is tightly related to the survival program of their nontransformed precursor cells. In the majority of nonHodgkin BCLs, the oncogenic program is established as an error of normal GC processes (ie, somatic hypermutation and class switch recombination), which facilitate mutations of tumor suppressor genes and translocation of oncogenes. 11 Execution of the oncogenic program in these lymphomas requires the maintenance of the GC program and the prevention of post-GC differentiation steps (eg, by BCL6 and PAX5 translocation) 12 and probably by deregulation of other transcription factors regulating GC phenotype and terminal differentiation of B cells. 13 Unlike other types of BCLs, neoplastic cells of classical Hodgkin lymphoma (cHL) lose most of their B-cell phenotype. 14 At the same time, Hodgkin and Reed-Sternberg (HRS) cells express many genes of activated B cells, indicating that the oncogenic program of cHL may arise in the process of deregulation of mechanisms, controlling activity of NF-B, 15 ERK, 16 and JAK/STAT 17 pathways in activated B cells. In addition, AKT and ERK kinases are frequently constitutively activated in different B-lymphoma entities, including follicular lymphoma (FL), 18 diffuse large BCL (DLBCL), 19 Burkitt lymphoma (BL), 20 and cHL. 21,22 Therefore, it has been hypothesized that FOXO1 inactivation might be a common event contributing to lymphomagenesis in several lymphoma entities. 8 Given the proposed critical role of inactivation of FOXO1 function in BCLs, we investigated FOXO1 expression in different BCL entities. Unexpectedly, whereas FOXO1 expression was maintained in majority of non-Hodgkin lymphomas (NHLs), downregulation was observed in cHL and lymphocyte-predominant Hodgkin lymphoma (LPHL). We found that re-expression of FOXO1 inhibited proliferation and induced apoptosis in ...
Primary mediastinal B-cell lymphoma (PMBL) is a well-defined subtype of diffuse large B-cell lymphoma. Molecular cytogenetics revealed frequent gains of 9p24. JAK2, mapping in this region, is presently regarded as a candidate oncogene because expression profiling showed high Janus kinase-2 (JAK2) transcript levels and JAK2 was found to be constitutively phosphorylated in mediastinal B-cell lymphomas. We confirm that in the MedB-1 mediastinal B-cell line, harboring a trisomy 9, JAK2 transcription is elevated and the product is highly
We tested in B6 mice whether the local expansion of CD4 T cells producing proinflammatory cytokines including IL-17 (Th17 cells) in the colonic lamina propria (cLP) depends on the commensal microflora. High numbers of CD4 Th17 cells were found in the lamina propria of the ileum and colon but not the duodenum, jejunum, mesenteric lymph nodes, spleen, or liver of specific pathogen-free (SPF) mice. The microflora is required for the accumulation of cytokine (IL-17, IFN-␥, TNF-␣, IL-10)-producing CD4 T cells in the cLP because only low numbers of cytokine-producing cLP CD4 T cells were found in syngeneic (age-and sex-matched) germfree mice. The fraction of cLP Th17 cells was higher in (type I and type II) IFN-but not IL-4-or IL-12p40deficient SPF congenics. cLP CD4 Th17 cells produce IL-17 but not IFN-␥, TNF-␣, IL-4, or IL-10. cLP CD4 Th17 cells accumulate locally in colitis induced by adoptive transfer of IFN-␥ ؉/؉ or IFN-␥ ؊/؊ CD4 T cells into congenic SPF (but not germfree) RAG ؊/؊ hosts. In this colitis model, cLP CD4 T cells that "spontaneously" produce IL-17 progressively increase in number in the inflamed cLP, and increasing serum IL-17 levels appear as the disease progresses. Commensal bacteria-driven, local expansion of cLP CD4 Th17 cells may contribute to the pathogenesis of this inflammatory bowel disease.
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