慢性炎症和肥胖是导致肝癌的重要风险因素，代谢应激与炎症平行或交互调节肝癌发生、发展。本研究小组近期工作报道，应激蛋白TRB3与自噬受体蛋白P62相互作用，介导自噬和蛋白酶体系统交互抑制，促进糖尿病相关肿瘤进程。我们还发现，敲低肝癌细胞TRB3，降低肿瘤干细胞标志蛋白表达，抑制巨噬细胞M2型极化。此外，TRB3与巨噬细胞迁移抑制因子（MIF）相互作用，增强MIF稳定性。我们因此提出假说：代谢应激诱导TRB3表达增高，增加的TRB3与MIF相互作用增强MIF稳定性，进而促进肿瘤相关巨噬细胞M2极化，诱导和维持肿瘤干细胞样特性，促进肝癌发生、发展。为此，我们将从整体动物－细胞－分子三个层次，结合肝癌临床样本，阐明TRB3通过调节肿瘤免疫微环境和肿瘤干性，在肥胖相关肝癌发生、发展中的作用和机制，并探索肝癌免疫治疗新策略。本研究揭示的代谢应激促肝癌的分子机制将为肝癌的防治和药物研发提供新的思路。

Chronic inflammation and obesity are associated with increased risk of hepatocellular carcinoma. Metabolic stresses and immune factors participate parallelly and reciprocally in the regulation of tumorigenesis and tumor progression of hepatocellular carcinoma. Recently, we reported that TRB3, a stress-induced protein, links insulin/IGF to tumor promotion by interacting with p62 and impeding autophagic/proteasomal degradations. We then identified that depletion of TRB3 inhibits the M2 polarization of tumor-associated macrophage (TAM) and decreases the expression of cancer stem cell markers. We also found that TRB3 is a binding partner of macrophage migration inhibitory factor (MIF) and increases the stability of MIF. We therefore hypothesize that metabolic stress-increased TRB3 connects metabolic factors to hepatocellular carcinogenesis and progression through inducing TAM recruitment and M2 polarization as well as enhancement of cancer stem cell-like properties. To prove this hypothesis, we’ll pursuit the potential roles and mechanisms of TRB3 in the regulation of macrophage polarization and cancer stem cell-like properties by using molecular & cellular technologies and animal models, in combination with clinical samples analysis. We'll also explore the therapeutic strategy of repolarizing macrophage for liver cancer treatment. Our proposed studies may not only provide deep insights into the pathogenesis of metabolic/immune stresses in the promotion of hepatocellular carcinogenesis and progression but also provide clues and opportunities for the development of anti-cancer drugs.