Expression data from pairwise non-tumor and tumor liver of -MYC and C-MYC/REG3A transgenic mice. Expression data from pairwise non-tumor and tumor liver of -MYC and C-MYC/REG3A transgenic mice

Antimicrobial proteins of the REG3 family represent, like a wide variety of C-type lectins to which they belong, the first line of protection against infections and transformed cells. Their expression is inducible, particularly in response to inflammation, making their role in cancer biology less clear and controversial, as an immune-inflammation background may pre-exist or co-exist. We show that REG3A presents a suppressive role of REG3A in hepatocellular carcinoma (HCC) in a mouse models of HCC driven by c-MYC. By comparing the transcriptional profiles of liver tumors from MYC-REG3A-TG mice with those from MYC-TG mice, we found that MYC-REG3A tumors belonged to the S3 and G5 molecular subclasses of the human HCC classification proposed by Hoshida et al. and Boyault et al., respectively, subclasses that concentrate well-differentiated and CTNNB1-mutated HCCs. Tumors from MYC-TG mice exhibited features of S1 and G2/G3 subclasses. Results of the GSEA analysis indicate marked differential gene expression profiles. MYC-REG3A tumors and adjacent liver are enriched in metabolic pathways including bile acid, xenobiotic, and fatty acid metabolism, oxidative phosphorylation, and activation of Wnt/β-catenin signaling, whereas transcriptional reprogramming of MYC-TG mouse livers resulted in activation of cell cycle-, inflammation-, and glycolysis-related pathways as expected. Overall design: Pairwise non-tumor and tumor liver tissues from 4 C-MYC and 4 C-MYC/REG3A transgenice mice were analysed

REG3家族抗菌蛋白与其所属的众多C型凝集素（C-type lectins）一样，是抵御感染与转化细胞的第一道防线。它们的表达具有可诱导性，尤其在炎症刺激下；由于免疫炎症背景可能预先存在或伴随存在，其在癌症生物学中的功能尚未明确且颇具争议。
本研究在c-MYC驱动的肝细胞癌（hepatocellular carcinoma, HCC）小鼠模型中证实，REG3A对肝细胞癌具有抑制作用。通过对比MYC-REG3A转基因（MYC-REG3A-TG）小鼠与MYC转基因（MYC-TG）小鼠的肝肿瘤转录组特征，我们发现MYC-REG3A组肿瘤分别归属于Hoshida等人与Boyault等人提出的人类肝细胞癌分子分型中的S3与G5亚型——该两类亚型均富集高分化且携带CTNNB1突变的肝细胞癌。而MYC-TG小鼠的肝肿瘤则呈现S1与G2/G3亚型的特征。
基因集富集分析（Gene Set Enrichment Analysis, GSEA）结果显示两组样本存在显著的基因表达谱差异：MYC-REG3A组肿瘤及其邻近肝组织富集于胆汁酸代谢、异生物质代谢、脂肪酸代谢、氧化磷酸化以及Wnt/β-连环蛋白信号通路激活等代谢通路；而MYC-TG小鼠肝组织的转录重编程则如预期般激活了细胞周期、炎症及糖酵解相关通路。
实验整体设计：本研究分析了4只C-MYC转基因小鼠与4只C-MYC/REG3A双转基因小鼠的配对非肿瘤肝组织与肿瘤肝组织样本。