D within a time-dependent manner right after birth. These data suggest that the quantity of HIF-1alpha protein in HIF1A TG micewas regulated by each transcriptional and post-transcriptional modifications. Surprisingly, HIF1A TG mice didn’t show clear variations in serum erythropoietin concentration or peripheral-Figure 3. The amount of intestinal tumors in HIF1A TG mice. The number of enlarged Peyer’s patches per mouse (size greater than three mm, determined by Methylene Blue staining) improved in both the tiny intestine (A) and colon (B) of HIF1A TG mice, compared with that located in wildtype or BALB/c mice (p,0.01 and 0.05, respectively). doi:10.1371/journal.pone.0057833.gPLOS One particular | www.plosone.orgDevelopment of Lymphoma by HIF-1alphaFigure four. Monoclonal rearrangement of T cell receptor gene within a tumor inside a HIF1A TG mouse. (A) A mouse showing enlarged peritoneal lymph nodes and hepatosplenomegaly. Monoclonality of proliferating lymphocytes was analyzed by flow cytometry with double staining utilizing CD3 and CD19 (B), or CD4 and CD8 (C). (D) Monoclonal rearrangement of TCR gene in lymphocytes from a peritoneal lymph node and spleen. (E) PCR utilizing primer sets certain for V, D, and J regions of T cell receptor (TCR) gene. doi:ten.1371/journal.pone.0057833.gblood red cell counts, in spite of of in vitro experiments demonstrating that human HIF-1alpha expression could activate HRE containing promoter inside a mouse cell line. A further investigation is necessary to clarify these findings. The main phenotypical abnormality observed in HIF1A TG mice was development of lymphoproliferative diseases, which appeared from 3 months soon after birth. The majority of those tumors had been located in the intestine, but some tumors displayed involvement in various organs accompanied with peripheral blood infiltration. Histological findings indicated that the proliferating lymphocytes evidenced a monotonous phenotype by immunohistochemistry and invaded from the lymph node capsules Table 1.Zolbetuximab Incidence of lymphoproliferative issues in transgenic mice.TG mice Homo (n = 16)Lymphoproliferative illness 12/16 (81 )Lymphoma (B, T, non B/T) 7/16 (44 ) (five, 1, 1)Hetero (n = 21) 17/21 (81 )8/21 (38 ) (5, 1, 2)Wild (n = 12)2/12 (17 )1/12 (8 ) (1, 0, 0)Monoclonality assessed by IgH or TCR rearrangement and/or systemic involvement of lymphoid cells was diagnosed as lymphoma. doi:ten.1371/journal.pone.0057833.tinto the adjacent tissues. We defined such tumors as lymphoma and further investigated the rearrangement patterns of TCR and IgH genes.Paricalcitol Monoclonal rearrangements of tumor-related genes in these tumors have been uncommon, although 1 tumor showed a highly aggressive phenotype and was identified to possess a single rearrangement band for TCR gene (Fig.PMID:24635174 4D, E). These results recommend that constitutive expression of HIF-1alpha promotes the occurrence of lymphoproliferative ailments, resulting in progression to overt lymphoma. Even though the precise function of HIF-1alpha in lymphomagenesis is not clear at present, it is inferred that HIF-1alpha acts as a tumor promoter since the occurrence of lymphoma is obtaining extended latency events. Some recent reports recommend that HIF2alpha also acts as a tumor promoter, in both in vitro and in vivo (Tp53H/H mouse) models [291]. In our mouse model, HIF2alpha level was not altered by HIF-1alpha overexpression, indicating either that HIF-2alpha will not be critical for spontaneous tumorigenesis within the Tp53H/H mouse model, or that HIF-2alpha overexpression promotes tumor formation only in susc.
