Roles of Reg protein in the pathophysiology of ulcerative colitis

最近，利用DNA阵列进行的综合分析一再证实，REG家族基因是在溃疡性结肠炎(UC)组织中过度表达的新基因。在预先设定的研究中发现，在UC组织中，Reg Iα基因的表达水平明显高于正常结肠黏膜，并且与UC组织的炎症程度显著相关。此外，Reg Iα蛋白不仅在UC相关癌(结肠癌)中强烈表达，而且在长期存在癌症高危发展的UC患者的癌前病变中也有强烈表达。关于Reg Iα基因表达的调控机制，已阐明-14 2位和-13 4位元件是IL-6诱导的Reg Iα启动子激活的原因，提示IL-6/STAT3信号通路对体外培养的癌细胞中Reg Iα基因的表达起关键作用。在生物学功能方面，我们阐明了Reg Iα蛋白在UC结肠癌中作为促有丝分裂因子和/或抗凋亡因子，通过激活Akt/Bcl2或Bclxl信号通路发挥抗凋亡作用。因此，REG Iα蛋白可能介导了STAT3信号转导的抗细胞凋亡作用。研究发现，REG IV和REG Iα蛋白在UC、癌前异型增生和结肠癌中高表达，对结肠癌细胞具有促生长和/或抗凋亡作用。然而，碱性成纤维细胞生长因子和角质形成细胞生长因子可促进UC粘膜中REG IV基因的表达，但不能被细胞因子刺激。综上所述，REG家族蛋白在UC结肠癌序列中起着促生长和/或抗凋亡因子的作用，其表达可能成为预测UC患者结肠癌发生发展的有用标志物。

Recently, comprehensive analyses using DNA array repeatedly confirmed that Reg family genes are novel genes overexpressed in ulcerative colitis (UC) tissues. In the preset study the level of REG Iα gene expression was found to be much higher in UC mucosa than in normal colonic mucosa and furthermore correlated significantly with severity of inflammation in UC tissues. Moreover, REG Iα protein was strongly expressed not only in UC-associated cancer (colitic cancer) but also in precancerous dysplastic lesions in longstanding UC patients with high risk for cancer development. Regarding the regulatory mechanism for REG Iα gene expression, it was clarified that the element from position -142 and -134 is responsible for IL-6 induced-REG Iα promoter activation and suggested that IL-6/STAT3 signaling is crucial for REG Iα gene expression in cancer cells in vitro. As for the biological functions, we clarified that REG Iα protein acts as a mitogenic and/or an anti-apoptotic factor in UC-colitic cancer sequence and exerts its anti-apoptotic effect by activating Akt/Bcl-2 or Bcl-xL signaling. Thus, REG Iα protein may mediate anti-apoptotic effect of STAT3 signaling. REG IV as well as REG Iα protein was clarified to be overexpressed in UC, precancerous dysplasia and colitic cancer lesions and functioned as a growth-promoting and/or anti-apoptotic factor for colon cancer cells. However, REG IV gene expression was enhanced by basic-fibroblast growth factor and keratinocyte growth factor but not by cytokines stimulation in UC mucosa. In conclusions, REG family proteins act as a growth-promoting and/or anti-apoptosis factor in UC-colitic cancer sequence and its expression is possible to be a useful marker to predict a development of colitic cancer in UC patients.