sorafenib抑制肝癌细胞EMT和肿瘤转移的分子机制及其表观遗传学研究

As one of the most common types of human diseases, liver cancer is the third leading cause of cancer mortality worldwide, with an annual death toll of approximately 700000. Currently, epithelial-mesenchymal transition (EMT) is considered to be a key step for cancer metastasis, in which transforming growth factor-beta (TGF-beta) is a pivotal inducer. In the past decade, the introduction of the multikinase inhibitor sorafenib as the first drug with therapeutic efficacy against advanced hepatocellular carcinoma (HCC) represents the biggest therapeutic progress. Aside from the established effects of sorafenib for the potent inhibition of tumor growth and angiogenesis in a variety of tumor types, it must have a much broader function than currently known. Previously, we uncovered a novel capacity of sorafenib to inhibit EMT and cell migration in hepatocytes and HCC cells. However, a detailed understanding of the underlying molecular mechanism and its effects on the epigenetic changes during EMT process largely remains unknown. In this project, we will identify a novel downstream target and explore its biological function during EMT and cancer metastasis both in vivo and in vitro. Additionally, we will evaluate the effects of sorafenib on the epigenetic changes of EMT in HCC cells and provide a potential interpretation for the underlying molecular mechanism. Certainly, these studies will shed light on the clinical benefits of sorafenib in the treatment of advanced HCCs and provide new evidence for the development of molecular targeted therapies against cancer.

肝癌是最常见的疾病之一，每年近70万人的死亡病例使其位于癌症死亡率的第三位。上皮-间质细胞转化（EMT）是肿瘤转移的关键步骤，而TGF-beta信号是肿瘤细胞微环境中最重要的EMT诱导因子。作为多靶点的激酶抑制剂，sorafenib已被批准用于晚期肝癌的治疗，是近年来肿瘤防治的重大进展。我们已证明sorafenib抑制肝癌细胞EMT和细胞迁移，并基于已有的基因表达谱分析，筛选发现凝血酶调节蛋白（TM）等多个下游分子。在本项目中，我们将进一步研究sorafenib是否通过调控TM的表达来抑制肝癌细胞EMT和肿瘤转移，并在体外和体内两方面阐明这一作用的分子机制；同时，我们还将在全基因组水平上筛查sorafenib对肝癌细胞EMT过程中表观遗传学的作用，发现基于EMT的新分子，为开发靶向EMT关键分子的治疗手段提供理论和实验基础。

包括肝细胞癌在内的上皮来源恶性肿瘤是威胁人类健康的重大杀手。上皮-间质细胞转化（EMT）是肿瘤转移的关键步骤，而TGF-beta信号是肿瘤细胞微环境中最重要的EMT诱导因子。作为多靶点的激酶抑制剂，sorafenib已被批准用于多种晚期癌症的临床治疗，是近年来肿瘤防治的重大进展。在本项目中，我们证明sorafenib抑制包括肝细胞癌在内的上皮来源癌细胞EMT、细胞迁移和胶原合成。另外，我们通过ChIP-seq分析sorafenib对细胞EMT过程中组蛋白修饰和表观遗传学的作用，筛选发现多个下游效应分子。这些研究为今后开发靶向EMT关键分子的治疗手段提供理论和实验基础。