Inflammatory bowel diseases are known to be the origin of colitis-associated colon cancer (CAC). We previously reported that dextran sulfate sodium (DSS)–induced colitis is exacerbated in mouse-IL-21-isoform transgenic (Tg) mice. In this study, we assessed the CAC development induced by azoxymethane (AOM) and DSS in our Tg mice. AOM-DSS–induced tumor development was dramatically increased in the Tg mice compared with wild-type mice. IL-21 is known to enhance activation-induced cytidine deaminase (AID) expression in B cells and induce Ab class switching. In contrast, the AID expression in cells other than B cells initiates tumor development in many tissues. Therefore, we investigated whether IL-21 induces the AID expression in the large intestinal epithelial cells (IECs) during CAC development. AID gene and protein expression was increased in the IECs of AOM-DSS– or DSS-treated Tg mice compared with those of wild-type mice. Furthermore, we confirmed IL-21 induced AID gene expression in the purified IECs ex vivo. The present study also showed IL-21R gene expression in unstimulated wild-type mouse IECs, and this gene expression was augmented by TNF-α stimulation. The IL-21R expression and IL-21–induced AID gene activation were further confirmed in the Colon-38 cell line. Taken together, IL-21 may be involved in increasing the risk of CAC by enhancing the AID expression in IECs.

Background: The regulation of the redox balance in the tumor microenvironment is thought to be an adaptive response of tumor cells to hypoxic environments. In recent years, it has been reported that the hemoglobin β-chain (HBB), which is involved in scavenging reactive oxygen species (ROS), is expressed in several carcinomas. However, the relationship between HBB expression and the prognosis of renal cell carcinoma (RCC) remains unclear. Methods: HBB expression was immunohistochemically analyzed in 203 nonmetastatic clear cell RCC (ccRCC) cases. Cell proliferation, invasion, and ROS production were measured in ccRCC cell lines treated with HBB-specific siRNA. Results: The prognosis of HBB-positive patients was worse than that of HBB-negative patients. Cell proliferation and invasion were inhibited, and ROS production was increased by treatment with HBB-specific siRNA. Oxidative stress increased HBB expression in cells exposed to H₂O₂. Conclusions: HBB expression in ccRCC contributes to cancer cell proliferation by suppressing ROS production under hypoxic conditions. Taken together with clinical results and in vitro experiments, HBB expression may serve as a new prognostic biomarker for RCC in the future.

A better understanding of pathogenic mechanisms is required in order to treat diseases. However, the mechanisms of diabetes mellitus and diabetic complications are extremely complex. Immune reactions are involved in the pathogenesis of diabetes and its complications, while diabetes influences immune reactions. Furthermore, both diabetes and immune reactions are influenced by genetic and environmental factors. To address these issues, animal models are useful tools. So far, various animal models of diabetes have been developed in rats, which have advantages over mice models in terms of the larger volume of tissue samples and the variety of type 2 diabetes models. In this review, we introduce rat models of diabetes and summarize the immune reactions in diabetic rat models. Finally, we speculate on the relationship between immune reactions and diabetic episodes. For example, diabetes-prone Biobreeding rats, type 1 diabetes model rats, exhibit increased autoreactive cellular and inflammatory immune reactions, while Goto-Kakizaki rats, type 2 diabetes model rats, exhibit increased Th2 reactions and attenuation of phagocytic activity. Investigation of immunological abnormalities in various diabetic rat models is useful for elucidating complicated mechanisms in the pathophysiology of diabetes. Studying immunological alterations, such as predominance of Th1/17 or Th2 cells, humoral immunity, and innate immune reactions, may improve understanding the structure of amplification circuits for diabetes in future studies.

Recent studies have discovered a relationship between glycosylphosphatidylinositol (GPI)-anchored protein 80 (GPI-80)/VNN2 (80 kDa GPI-anchored protein) and malignant tumors. GPI-80 is known to regulate neutrophil adhesion; however, the action of GPI-80 on tumors is still obscure. In this study, although the expression of GPI-80 mRNA was detectable in several tumor cell lines, the levels of GPI-80 protein were significantly lower than that in neutrophils. To clarify the function of GPI-80 in tumor cells, GPI-80-expressing cells and GPI-80/VNN2 gene-deleted cells were established using PC3 prostate cancer cells. In GPI-80-expressing cells, GPI-80 was mainly detected in vesicles. Furthermore, soluble GPI-80 in the conditioned medium was associated with the exosome marker CD63 and was also detected in the plasma obtained from prostate cancer patients. Unexpectedly, cell adhesion and migration of GPI-80-expressing PC3 cells were not modulated by anti-GPI-80 antibody treatment. However, similar to the GPI-80 family molecule, VNN1, the pantetheinase activity and oxidative state were augmented in GPI-80-expressing cells. GPI-80-expressing cells facilitated non-adhesive proliferation, slow cell proliferation, NF-κB activation and IL-1β production. These phenomena are known to be induced by physiological elevation of the oxidative state. Thus, these observations indicated that GPI-80 affects various tumor responses related to oxidation.