TRAIL特异性诱导肿瘤细胞凋亡的功能使其具有广阔临床应用前景，然而肿瘤细胞的固有耐药作用阻碍了其广泛应用。申请人前期研究发现：干扰素刺激基因ISG12a在敏感肝癌细胞株LH86中表达显著高于耐药细胞株Huh7，且调控TRAIL诱导的肝癌细胞凋亡，但是ISG12a调控TRAIL诱导肝癌细胞凋亡的下游具体分子机制未明。我们的前期研究及预实验结果表明TRAIL可以激活敏感细胞株中线粒体凋亡通路，提示ISG12a通过激活线粒体通路增强TRAIL诱导的肝癌细胞凋亡。预实验结果同时证实ISG12a与孤儿核受体NR4A1相互作用并在肝癌细胞中共定位。本课题将以细胞模型和动物模型为基础来研究ISG12a如何通过与NR4A1相互作用来增强TRAIL的抗肿瘤功能，深入探讨ISG12a增强TRAIL诱导肝癌细胞凋亡的具体分子机制，为肝癌细胞对TRAIL的固有耐药机制提供新的理论基础。

TRAIL selectively induces cancer cell apoptosis, making it a promising candidate in clinical applications. Nevertheless, resistance to TRAIL-induced apoptosis in cancer cells is one impediment to the use of TRAIL-based agents as anti-tumor drugs. Our previous study find that IFN-stimulated gene ISG12a is highly expressed in TRAIL-sensitive LH86 cells compare to in TRAIL-resistant Huh7 cells and regulates TRAIL-induced apoptosis, but the underlying mechanisms are still unclear. We also find that TRAIL actives mitochondria-dependent intrinsic apoptotic pathway in sensitive cells. These findings suggest that ISG12a augments TRAIL-induced apoptosis by activating mitochondrial pathway. Our preliminary results indicate that ISG12a interacts and co-localizes with orphan receptor NR4A1 in HCC cells. In the present study we will investigate the mechanisms by which ISG12a increases TRAIL sensitivity based on cell and animal models. We will study how ISG12a enhances antitumor effects of TRAIL by interacting with NR4A1, hence offering a new theoretical basis for congenital resistance mechanism of HCC cells to TRAIL.