肝细胞癌的细胞起源研究

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. It is a major malignant tumor in the liver and mainly occurs in patients with chronic liver disease and cirrhosis. HCC is morphologically heterogeneous, suggesting that there may be different cellular origins of hepatocellular carcinoma. In addition, there are many different subpopulations of hepatocytes, suggesting that different subpopulations of hepatocytes may have different preferences for the formation of hepatocellular carcinoma. However, the cellular origins of HCC remain unclear currently. Here we used Dre-rox and Cre-loxP dual homologous recombinase system to achieve more subtle labeling of the different subpopulations of hepatocytes and, for the first time, simultaneous labeling of different subpopulations in the same mouse, to systematacially study the differences in ability of different subpopulations of hepatocytes to form HCC. In addition, we combined cell tracking with gene knock-in technology to construct a tumor model that mimics the development of human hepatocellular carcinoma and trace the fate of both hepatocytes and biliary epithelial cells in this model to explore the cellular origin and molecular mechanisms of hepatocellular carcinoma. This work will provide strong technical support for the research on liver development and regeneration and liver oncology, reveal the cellular origin of HCC and analyze its potential molecular mechanism, provide an important theoretical basis and scientific basis for the clinical treatment of HCC.

肝细胞癌（HCC）是肝脏的主要恶性肿瘤，主要发生在慢性肝病和肝硬化患者中，是全球最为常见的恶性肿瘤之一。HCC在形态上呈异质性，提示肝细胞癌可能存在多种起源。此外，肝细胞存在多种不同亚群，也提示不同亚群的肝细胞在形成肝细胞癌上可能具有不同的偏好性。然而，目前有关HCC的细胞起源仍不清楚。我们利用Dre-rox和Cre-loxP双同源重组酶系统达到更为精细的标记肝细胞的多个亚群，并首次实现在同一只小鼠内同时标记不同亚群，系统研究不同亚群的肝细胞形成HCC能力的差异。此外，我们将细胞示踪和基因敲入技术结合起来，构建了一种模拟人类肝细胞癌发生的肿瘤模型，并在该模型中同时追踪肝细胞和胆管上皮细胞的命运，探究肝细胞癌发生的细胞起源和分子机制。该研究将为肝脏发育与再生及肝脏肿瘤研究等领域提供强大的技术支持，同时揭示HCC的细胞起源并解析其潜在的分子机制，为HCC的临床治疗提供重要的理论基础和科学依据。

肝细胞癌(HCC)是肝脏的主要恶性肿瘤，主要发生在慢性肝病和肝硬化患者中，是全球最为常见的恶性肿瘤之一。HCC在形态上呈异质性，提示肝细胞癌可能存在多种起源。此外， 肝细胞存在多种不同亚群，也提示不同亚群的肝细胞在形成肝细胞癌上可能具有不同的偏好性 。然而，目前有关HCC的细胞起源仍不清楚。在本研究中，我们构建了多种标记不同肝细胞亚群的遗传谱系示踪新工具，同时利用基于Dre-rox和Cre-loxP双同源重组酶系统实现了同时在同一只小鼠中追踪不同的肝细胞亚群。我们在新的遗传工具小鼠中诱导HCC的形成，研究不同肝细胞亚群对HCC的贡献。结果显示HCC主要起源于位于中央静脉的周围的肝细胞，门静脉周围的肝细胞则很少贡献HCC的形成。该研究揭示了HCC的细胞起源，为HCC的临床治疗提供重要的理论基础和科学依据。