MAPEG与炎症介质生成相关。申请者已发现肝脏MAPEG表达区存在NF-κB入核及靶向抑癌基因microRNAs下调，并据此构建了胚胎干细胞定向分化肝组织炎症模型。该模型呈完整的肝组织结构和固有的炎症向肿瘤转化信号通路，及肝成体干细胞癌变病因学特征，使肝脏炎症向肿瘤转化的网络调控更具多元化。申请者尚发现喹唑啉咪唑化合物可通过抑制EGFR而呈促分化抑肿瘤双重作用，提示可能经由与IL-6R并行的EGFR-STAT3通路。本项目拟在前期工作基础上，提出肝成体干细胞在炎症区易被TGF-β/microRNA调控向肿瘤转化假说，进一步论证“炎症-成体干细胞-恶性转化”三者关联的TGF-β-microRNA炎症馈路调控肝癌发生研究新体系。旨在从转化医学的角度，揭示肝脏MAPEG介导的炎症转化肝细胞癌生命现象本质，及药物干预潜在靶点，争取在“炎症向肿瘤转化调控网络研究的新方法”这一核心科学问题上有所突破。

Transforming growth factor (TGF-β) is essential for liver development and hepatocyte function, and disruption of TGF-β signaling is critical to the development of hepatocellular cancer (HCC). p53-dependent stem cell apoptosis and G1 arrest are linked by TGF-β. Embryonic stem cells, hepatic stem cells, and liver development are linked by common pathways. Here, we set up a modol using stem cell-derived hepatic tissue system based on MAPEG expression. We are going to explore whether transient inhibition of TGF-β initiates hepatocellular transformation through a microRNA inflammatory feedback loop circuit consisting of miR-137, interleukin-6, epidermal growth factor receptor (EGFR), STAT3, miR-871, and miR-883b. Moreover, we show that, once this circuit is activated, it maintains suppression of TGF-β and sustains oncogenesis. Systemic administration of miR-137 or EGFR inhibitors might modulate inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this TGF-β circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.