Gene expression network for tumor suppression

在目前的研究中，我们从遗传学和表观遗传学两个方面对肿瘤发生的分子机制进行了多方面的研究，不仅分析了参与肿瘤抑制的分子之间的相互关系，而且分析了基因表达网络。具体地说，我们发现由组成性产生的干扰素-α/β在干扰素-γ或IL-6介导的细胞反应以及癌症预防的调节系统中发挥的几个重要作用。我们还发现了RANKL和干扰素-γ之间的一种新的串扰机制，阐明了干扰素系统在破骨细胞分化中的调节作用，为其在转移性肿瘤的骨破坏方面提供了潜在的治疗应用。在缺乏IRF-2的小鼠中观察到自身免疫性疾病的发生，IRF-2是干扰素-a/β信号的衰减器。进一步的分析揭示了干扰素-α/β信号在调节CD8~+T细胞应答中的作用。在这些irf-2缺陷的小鼠中，这种过度活跃的…更多的干扰素-α/β信号影响树突状细胞的正常分化。干扰素-α/β信号在DC成熟过程中也是不可或缺的。此外，另一个IRF家族成员IRF-7被证明是血浆细胞样树突状细胞在非甲基化DNA(CpG)刺激下诱导干扰素的必需转录因子，而CpG被认为是一种有效的抗肿瘤免疫佐剂。我们还发现了一种时空调节机制，即浆细胞样树突状细胞能够高水平地产生干扰素-α/β。另一方面，IRF-5也被发现主要参与CpG诱导的促炎细胞因子的产生。此外，我们还发现了新的P53靶基因NoxA和Reprimo，它们分别参与了P53介导的细胞凋亡或细胞周期停滞。通过产生NOXA缺陷小鼠的进一步研究表明，NOXA可能是一个有益的治疗靶点，因为它在表达癌基因的细胞中经历了选择性的凋亡。最后，我们发现了干扰素-α/β信号与P53介导的反应之间的相互关系，这为肿瘤抑制与免疫之间的联系提供了一个新的方面。综上所述，我们相信这些研究成果有助于理解肿瘤抑制的分子机制，并为其临床应用提供分子基础。较少

In the current study, we have made multifaceted approach to elucidate molecular mechanisms for oncogenesis, by analyzing not only the interrelationships between molecules which are involved in tumor suppression but also the gene expression network from both genetic and epigenetic aspects. Specifically, we found several important roles of "weak signal" by constitutively produced IFN-α/β in IFN-γ or IL-6-mediated cellular response as well as regulatory systems for cancer prevention. We also found a novel cross-talk mechanism between RANKL and IFN-γ, and clarified the regulatory role of the IFN system in osteoclast differentiation, which provided its putative therapeutic application to bone destruction by metastatic tumors. Development of autoimmune-like disease was observed in mice lacking IRF-2, which is an attenuator of IFN-a/β signaling. Further analyses revealed the role of IFN-α/β signaling in the regulation of CD8^+ T cell response. In these IRF-2-deficient mice, such hyperactivati … More on of IFN-α/β signaling affects normal differentiation of dendritic cells. IFN-α/β signaling is also found to be indispensable during DC maturation. Furthermore, it was demonstrated that another IRF-family member, IRF-7, is an essential transcriptional factor for the IFN induction in plasmacytoid DCs in response to unmethylated DNA (CpG), which is known to be a potent adjuvant for anti-tumor immunity. And we found a spaciotemporal regulation, by which plasmacytoid DCs are capable to produce IFN-α/β at high levels. On the other hand, IRF-5 is also found to be essentially involved in the CpG-induced production of proinflammatory cytokines. In addition, we identified novel p53 target genes, Noxa and Reprimo, which are involved in p53-mediated apoptosis or cell cycle arrest, respectively. Further study by generating Noxa-deficient mice revealed that Noxa may be a beneficial therapeutic target since it undergoes selective apoptosis in oncogene-expressing cells. Finally, we found an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity.Taken together, we believe that these research accomplishments contribute to some advance in understanding molecular mechanisms underlying tumor suppression, and provide a molecular basis for their clinical applications. Less