Roles of Reg protein in the pathophysiology of ulcerative colitis

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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.