Aurora-A は細胞分裂期においてgeminin を安定化することで複製前複合体形成やDNA複製を制御する

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex (pre-RC) formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome ubiquitin ligase complex (APC/C), which targets geminin for proteasomal degradation to allow pre-RC formation. Conversely, from S to G2, geminin is stabilized thanks to APC/C inhibition to ensure inhibition of pre-RC formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-RC formation in the ensuing S phase. The Aurora-A-geminin-Cdt1 axis therefore represents a critical regulator of proper DNA replication.広島大学(Hiroshima University)博士(歯学)Philosophy in Dental Sciencedoctora

ROLE OF RUNX3 IN HEAD AND NECK CANCER

Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer

Virus Infections Play Crucial Roles in the Pathogenesis of Sjögren’s Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease especially targeting exocrine glands, such as the salivary and lacrimal glands. A radical therapy for SS based on its etiology has not been established because of the complex pathogenesis of the disease. Several studies have demonstrated a relationship between virus infection and SS pathogenesis. In particular, infection with the Epstein-Barr (EB) virus among others is a potent factor associated with the onset or development of SS. Specifically, virus infection in the target organs of SS triggers or promotes autoreactive responses involving the process of autoantigen formation, antigen-presenting function, or T-cell response. Our review of recent research highlights the crucial roles of virus infection in the pathogenesis of SS and discusses the critical association between virus infection and the etiology of autoimmunity in SS

Formation of Autoimmune Lesions Is Independent of Antibiotic Treatment in NOD Mice

The relationship between autoimmunity and changes in intestinal microbiota is not yet fully understood. In this study, the role of intestinal microbiota in the onset and progression of autoimmune lesions in non-obese diabetic (NOD) mice was evaluated by administering antibiotics to alter their intestinal microenvironment. Flow cytometric analysis of spleen cells showed that antibiotic administration did not change the proportion or number of T and B cells in NOD mice, and pathological analysis demonstrated that autoimmune lesions in the salivary glands and in the pancreas were also not affected by antibiotic administration. These results suggest that the onset and progression of autoimmunity may be independent of enteral microbiota changes. Our findings may be useful for determining the appropriate use of antibiotics in patients with autoimmune diseases who are prescribed drugs to maintain systemic immune function

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication

IFITM1 Promotes Invasion of HNSCC Cells

Purpose: Head and neck squamous cell carcinoma (HNSCC), one of the most common types of human cancer, show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with invasion of HNSCC remain poorly understood. We identified Interferon-induced transmembrane protein 1 (IFITM1) as a candidate gene for promoting the invasion of HNSCC by comparing the gene expression profiles between parent and a highly invasive clone. Therefore, we examined the role of IFITM1 in the invasion of HNSCC. Experimental Design: IFITM1 expression was examined in HNSCC cell lines and cases by RT-PCR and immunohistochemistry. IFITM1 overexpressing and knockdown cells were generated, and the invasiveness of these cells was examined by in vitro invasion assay. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells was examined by microarray. Results: HNSCC cells expressed IFITM1 mRNA at higher levels, while normal cells did not express. By immunohistochemistry, IFITM1 expression was observed in early invasive HNSCC and invasive HNSCC. Interestingly, IFITM1 was expressed at the invasive front of early invasive HNSCC, and higher expression of IFITM1 was found in invasive HNSCC. In fact, IFITM1 overexpression promoted and IFITM1 knockdown suppressed the invasion of HNSCC cells in vitro. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells revealed that several genes including matrix metalloproteinase were up-regulated in IFITM1 overexpressing cells. Conclusion: Our findings suggest that IFITM1 plays an important role for the invasion at the early stage of HNSCC progression, and that IFITM1 can be a therapeutic target for HNSCC

Impaired Function of Treg Cells

Neonatal thymectomy (Tx) in certain mouse strains is known to induce organ-specific autoimmunity due to impaired functions of T cells, including Foxp3+ regulatory T (Treg) cells in the thymus. The precise mechanism underlying the induction of autoimmunity by neonatal Tx remains unclear. One possibility is that depletion of Treg cells breaks down peripheral tolerance. We examined the functions of Treg cells by using a murine Sjögren’s syndrome (SS) model, NFS/sld mice that underwent neonatal Tx. The ratio of Treg cells to effector memory phenotype T cells in Tx mice was significantly lower than that of non-Tx mice. In addition, in vitro induction of peripherally induced Treg cells by transforming growth factor-β (TGF-β) using naïve T cells from SS model mice was severely impaired. The mRNA expression of TGF-β receptor I, II, and Smad3 and -4 in the TGF-β-induced signal transduction pathway of Treg cells in this SS model were lower than those of control mice. In addition, Treg cells in this SS model exhibited an IFN-γ-producing Th1-like phenotype that resembled effector T cells. In conclusion, these results suggest that abnormal expansion and differentiation of Treg cells and inflammatory cytokines produced by Treg cells contribute to the development of autoimmunity

Oral environment and cancer

Cancer is now the leading cause of death in Japan. A rapid increase in cancer mortality is expected as Japan is facing a super-aged society. Many causes of cancer are known to be closely linked to life style factors, such as smoking, drinking, and diet. The oral environment is known to be involved in the pathogenesis and development of various diseases such as bronchitis, pneumonia, diabetes, heart disease, and dementia. Because the oral cavity acts as the bodily entrance for air and food, it is constantly exposed to foreign substances, including bacteria and viruses. A large number of bacteria are endemic to the oral cavity, and indigenous oral flora act to prevent the settlement of foreign bacteria. The oral environment is influenced by local factors, including dental plaque, tartar, teeth alignment, occlusion, an incompatible prosthesis, and bad lifestyle habits, and systemic factors, including smoking, consumption of alcohol, irregular lifestyle and eating habits, obesity, stress, hormones, and heredity. It has recently been revealed that the oral environment is associated with cancer. In particular, commensal bacteria in the oral cavity are involved in the development of cancer. Moreover, Candida, human papilloma virus and Epstein-Barr virus as well as commensal bacteria have been reported to be associated with the pathogenesis of cancer. In this review, we introduce recent findings of the correlation between the oral environment and cancer

ヒト角化上皮細胞における5-FU誘発性酸化ストレスおよび炎症応答に対するresveratrolの保護効果

Although 5-fluorouracil (5-FU) is currently used as an anti-cancer chemotherapy, adverse effects such as oral mucositis potentially limit its clinical application. Additionally, the prevention of 5-FU-induced side effects are scarce. Resveratrol is known to decrease oxidative damage and inflammation. In this study, we examined the protective effects of resveratrol on 5-FU-induced oxidative stress and inflammatory responses in normal human keratinocytes (HaCaT cell) as in vitro oral mucositis model. HaCaT cells were exposed to 5-FU and simultaneously treated with resveratrol. The effects of resveratrol on 5-FU-induced cytotoxicity were evaluated using cell viability assay. The production of reactive oxygen species (ROS) was measured using a fluorescence spectrophotometer. The effects of resveratrol on nuclear factor erythroid 2-related factor 2 (Nrf2), silent information regulator transcript-1 (SIRT-1), and nuclear factor kappa B (NF-κB) signaling and inflammatory cytokine expression were examined. Resveratrol suppressed 5-FU-induced overproduction of ROS by upregulating anti-oxidant defense genes through Nrf2 activation and SIRT-1 expression. Concerning inflammatory responses, resveratrol suppressed the 5-FU-induced expression of pro-inflammatory cytokines via NF-κB nuclear translocation. Conversely, N-acetylcysteine reduced ROS levels without affecting the expression of pro-inflammatory cytokines. Resveratrol might be useful for preventing 5-FU-induced adverse effects by activating anti-oxidant and anti-inflammatory responses

RUNX3 Has an Oncogenic Role

Background: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor of cancer and appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Surprisingly, we found that RUNX3 expression level in head and neck squamous cell carcinoma (HNSCC) tissues, which is one of the most common types of human cancer, was higher than that in normal tissues by a previously published microarray dataset in our preliminary study. Therefore, here we examined the oncogenic role of RUNX3 in HNSCC. Principal Findings: Frequent RUNX3 expression and its correlation with malignant behavior were observed in HNSCC. Ectopic RUNX3 overexpression promoted cell growth and inhibited serum starvation-induced apoptosis and chemotherapeutic drug induced apoptosis in HNSCC cells. These findings were confirmed by RUNX3 knockdown. Moreover, RUNX3 overexpression enhanced tumorsphere formation. RUNX3 expression level was well correlated with the methylation status in HNSCC cells. Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells. Conclusions/Significance: Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC