Background and Aims: Antimicrobial proteins of the REG3 family provide a first line of protection against infections and transformed cells. Their expression is inducible by inflammation, which makes their role in cancer biology less clear, since an immune- inflammatory context may preexist or coexist with cancer, as occurs in hepatocellular carcinoma (HCC). The aim of this study is to clarify the role of REG3A in liver carcinogenesis and to determine whether carbohydrate-binding functions are involved. Approach and Results: This study provides evidence of the suppressive role of REG3A in HCC by reducing O-GlcNAcylation in two mouse models of HCC, in vitro cell studies, and in clinical samples. REG3A expression in hepatocytes significantly reduces global O- GlcNAcylation and O-GlcNAcylation of c-MYC in preneoplastic and tumor livers and markedly inhibits HCC development in REG3A-c-MYC double transgenic mice and in mice exposed to diethylnitrosamine (DEN). REG3A modifies O-GlcNAcylation without altering the expression or activity of OGT, OGA, or GFAT. Reduced O-GlcNAcylation was consistent with decreased levels of UDP-GlcNAc in pre-cancerous and cancerous livers. This effect is linked to the ability of REG3A to bind Glc and Glc-6P, suggested by a REG3A mutant unable to bind Glc and Glc- 6P and alter O-GlcNAcylation. Importantly, cirrhotic patients with high hepatic REG3A expression had lower levels of O-GlcNAcylation and longer cancer-free survival than REG3A- negative cirrhotic livers. Conclusion: REG3A helps fight liver cancer by reducing O-GlcNAcylation. This study suggests a new paradigm for the regulation of O-GlcNAc signalling in cancer-related pathways through interactions with the carbohydrate-binding function of REG3A.

中文翻译：

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靶向 O-GlcNAc 糖基化途径的抗菌凝集素 REG3A 的肿瘤抑制作用


背景和目的：REG3 家族的抗菌蛋白提供了针对感染和转化细胞的第一道保护。它们的表达可由炎症诱导，这使得它们在癌症生物学中的作用不太清楚，因为免疫炎症环境可能预先存在或与癌症共存，如肝细胞癌（HCC）中所发生的那样。本研究的目的是阐明 REG3A 在肝癌发生中的作用，并确定是否涉及碳水化合物结合功能。方法和结果：本研究通过减少两种 HCC 小鼠模型中的 O-GlcNAcylation 来证明 REG3A 在 HCC 中的抑制作用，体外细胞研究和临床样本。肝细胞中的 REG3A 表达显着降低肿瘤前和肿瘤肝脏中 c-MYC 的整体 O-GlcNAcylation 和 O-GlcNAcylation，并显着抑制 REG3A-c-MYC 双转基因小鼠和暴露于二乙基亚硝胺 (DEN) 的小鼠中的 HCC 发展。 REG3A 修饰 O-GlcNAcylation，而不改变 OGT、OGA 或 GFAT 的表达或活性。 O-GlcNAc 酰化的减少与癌前和癌变肝脏中 UDP-GlcNAc 水平的降低一致。这种效应与 REG3A 结合 Glc 和 Glc-6P 的能力有关，无法结合 Glc 和 Glc-6P 并改变 O-GlcNAcylation 的 REG3A 突变体表明。重要的是，与 REG3A 阴性肝硬化患者相比，REG3A 高表达的肝硬化患者 O-GlcNAc 酰化水平较低，无癌生存期较长。结论：REG3A 通过减少 O-GlcNAc 酰化来帮助对抗肝癌。这项研究提出了一种通过与 REG3A 的碳水化合物结合功能相互作用来调节癌症相关通路中 O-GlcNAc 信号传导的新范例。