Hippo信号通路参与TNF-α促进肝前体细胞异常激活的机制研究

Abnormal activation of hepatic progenitor cells (HPCs) was closely related to hepatocarcinogenesis. Hippo signaling played an important role in hepatocarcinogenesis. But the mechanisms of Hippo signaling in abnormal activation of HPCs remained elusive. In our previous study, we found that abnormal activation of HPCs depended on TNF-α. Firstly, using conditional gene knock out of TNF-α, in animal models for hepatoma and HPCs abnormal activation, we intend to observe the influence of Hippo signaling on HPCs abnormal activation induced by TNF-α; Secondly, definite the kind of TNF receptors which participate the regulation of Hippo signaling by TNF-α; The specific molecular mechanism of HPCs abnormal activation is further discussed. Screen the key molecular in the regulation of Hippo signaling by TNF-α; Finally, intervene and check the role of key molecular to clear the mechanism of Hippo signaling in abnormal activation of HPCs induced by TNF-α. These findings will provide the theoretical basis for Hepatocellular Carcinoma clinical diagnosis and treatment, improve our understanding of the mechanisms underlying hepatocarcinogenesis

肝前体细胞（HPCs）异常激活与肝癌发生密切相关。Hippo信号通路在肝癌发生中发挥重要作用，但在HPCs的异常激活中，Hippo信号通路的作用机制尚不清楚。本课题组前期研究发现，HPCs的异常激活依赖于TNF-α。本研究拟利用TNF-α敲除和基因沉默技术，分别在大鼠诱癌和HPCs的异常激活模型中，观察在TNF-α促进HPCs异常激活中Hippo信号通路的变化及作用；利用体内外实验，明确TNF-α通过何种TNFR调控Hippo信号通路；进一步筛选TNF-α调控Hippo通路的关键分子；反向干预、验证相关分子作用，明确Hippo信号通路参与TNF-α促进HPCs异常激活的分子机制。本研究有助于从微环境和干细胞的交互作用角度认识肝癌发生的规律及机制,为肝癌临床诊疗提供理论依据。

肝前体细胞（Hepatic progenitor cells, HPCs）凭借其自我更新和多向分化潜能在肝脏发育，损伤修复中发挥重要作用。在慢性炎症持续存在的恶劣微环境中，HPCs异常激活及向肿瘤细胞的恶性转化驱动肝癌的发生发展。肝癌是一种炎症相关性肿瘤，长期慢性炎症导致HPCs异常激活及恶性转化，并最终演化为肝癌细胞。本研究首次利用HPCs移植大鼠原发肝癌模型联合肝癌患者单细胞转录组测序观察HPCs异常激活及恶性转化过程，并证实了TNFR2对TNFα诱导的原发性肝癌至关重要。本课题将TNFR2确定为TNFα下游的特异性受体，驱动HPCs介导的原发性肝癌的发生发展，并证明TNFR2通过hnRNPK调节YAP的转录活性。hnRNPK与YAP直接结合并稳定目标基因位点上的YAP以促进其转录。本研究揭示了TNFR2-hnRNPK-YAP信号轴对于TNFα诱导的HPC异常激活与恶性转化至关重要，并强调了该轴与原发性肝癌发展的病理关联。该研究阐明了TNFRs在HPC介导的肝癌发生中的不同作用，进一步提示hnRNPK是TNFR2依赖性TNFα介导的炎症微环境和Hippo信号传导之间的重要生物分子纽带。明确TNFR2在介导HPC恶性转化过程中的关键作用及分子机制将为进一步寻找肝癌的早期治疗干预靶点提供理论依据。