TGF-β1诱导肝星状细胞转化为肿瘤相关成纤维细胞在肝癌侵袭转移中的作用研究

Hepatocellular carcinoma (HCC) is an aggressive malignancy worldwide. The survival rate of patients with HCC is predominantly influenced by the invasive and metastatic ability, in which cancer-associated fibroblasts (CAF) plays an important role. Hepatic stellate cell(HSC) is one kind of the main liver mesenchymal cells, and it is closely associated with the invasion and metastasis of HCC. According to our previous studies, the expression of α-SMA and FAP, the CAF markers, in mesenchymal cells of hepatocarcinoma tissues, is obviously correlated with the metastasis and prognosis of HCC. Meanwhile, we conclude that TGF-β1 can induce a higher expression level of α-SMA and FAP in hepatic stellate cells by upregulating Smad4 expression from the in vitro experiments.Based on the above, we hypothesize TGF-β1 could induce the transformation of HSC into CAF mediated by smad signaling pathway in the microenvironment of HCC, thus accelerating invasion and metastasis.So this research aims to verify that HSC will transformate into CAF, which further enhances the invansive and metastasic capacity in the microenvironment of HCC, and to investigate the possible mechanism of TGF-β1/Smads signaling pathway in this process.The results will contribute us to understand the effect of mesenchymal cells on invasion and metastasis of HCC better, What's more, they may help to provide new stategies for HCC prevention and treatment via microenvironmental approaches.

肝癌的侵袭转移是影响患者生存率的主要因素。肿瘤相关成纤维细胞（CAF）在肝癌侵袭转移中发挥重要作用。肝星状细胞（HSC）是肝脏主要的间质细胞之一，与肝癌侵袭转移密切相关。我们研究发现：CAF标记物α-SMA及FAP在肝癌间质中的表达与肝癌的转移及预后明显相关；细胞实验发现，TGF-β1可以上调肝星状细胞中Smad4表达，诱导CAF的标志分子α-SMA及FAP的表达升高。据此，我们提出如下假设：肝癌微环境中，TGF-β1通过Smad信号通路诱导HSC转化为CAF，从而促进肝癌的侵袭转移。本研究拟通过肝星状细胞与肝癌细胞体外三维共培养模型、裸鼠成瘤模型及人体肝癌组织标本，验证肝癌微环境中HSC向CAF转化并促进肝癌侵袭转移的现象，并探讨TGF-β1/Smads信号通路在其过程中的作用机制，研究结果将为探讨间质细胞在肝癌侵袭转移中的作用提供帮助，为从微环境途径寻找HCC防治新靶点提供思路。

TGF-β信号通路在肝癌发生发展中发挥重要作用，涉及机制十分复杂，但确切机制尚不清楚。我们前期研究发现，TGF-β通路参与肝癌细胞增殖侵袭、微血管形成过程，并与肝癌病理分期、转移及预后密切相关。本课题组始终紧紧围绕“肝癌微环境中，TGF-β1通过Smad信号通路诱导肝星状细胞（HSC）转化为肿瘤相关成纤维细胞（CAF），从而促进肝癌的侵袭转移”进行研究，经过全体课题组成员的共同努力，目前本课题的主要研究内容已经顺利完成，基本达到了预期研究目标，具体如下：本研究通过利用肝癌细胞和人体肝癌组织标本，证实（1）肝癌微环境中HSC可以转化为CAF并促进肝癌侵袭转移；（2）肝癌微环境中，TGF-β1促进HSC向CAF转化从而促进肝癌侵袭转移。通过以上这些研究，加深了对间质细胞在肝癌侵袭转移中作用的认识，本研究结果为从微环境途径寻找HCC防治新靶点提供实验依据，为今后肝癌的预防、诊断和治疗提供重要的参考。