激活LXR通路抑制肿瘤发生与发展的机理研究

Interferon gamma (IFNgamma) is an important cytokine and plays an critical role in anti-virus and anti-tumor. Liver X receptor (LXR) is a ligand-activated transcription factor. ERK1/2 are kinases demonstrating multiple functions in various biological processes, such as inflammation, tumorigenesis and immunology. In our preliminary studies, we observed that LXR ligand induced the production of IFNgamma in different tissues/cell types, particularly, in macrophages and T cells. Furthermore, the administration of LXR ligand to mice inhibited the growth of transplanted lung cancer cells in vivo, reduced the tumor-mediated mortality and morbidity. In contrast, all the above functions were not observed in IFNgamma knockout (IFNgamma-/-) mice suggesting the anti-tumor function of LXR ligand is mainly completed by inducing IFNgamma expression. Similarly, we observed that ERK1/2 inhibitors were able to induce IFNgamma expression, inhibit tumor development, and decrease the tumor-induced mortality and morbidity. Therefore, we propose a study entitled "The mechanisms for inhibition of tumor development by activation of LXR pathway". We anticipate that by completing these studies, we will be able to disclose the new function of LXR and discover a new theory for the development of a novel cancer therapy.

干扰素伽马(IFNgamma,IFNr)是抗病毒与肿瘤的重要细胞因子，肝X受体(liver X receptor,LXR)是配体(激动剂)激活的转录因子。ERK1/2为重要激酶，在炎症、肿瘤、免疫等方面发挥重要功能。我们的前期工作发现：LXR激动剂能强烈地诱导小鼠各组织尤其是巨噬细胞和T细胞中IFNr的表达，更进一步地我们发现LXR激动剂能明显地抑制移植肺肿瘤在体内的生长，降低肿瘤的发病率和致死率。然而上述各效果并不能在IFNr?敲除小鼠中发生。这些结果表明LXR激动剂主要是通过诱导IFNr来发挥抗肿瘤作用；同时我们发现抑制ERK1/2通路具有与激活LXR通路类似的功能，即诱导IFNr表达、抑制肿瘤生长，降低肿瘤的发病率和致死率。为此，我们提出 "激活LXR通路抑制肿瘤发生与发展的机理研究"。期待通过此研究揭示LXR通路新的生物功能，为防治肿瘤提供新策略和理论支持。

干扰素伽马(IFNgamma)是抗病毒与肿瘤的重要细胞因子，肝X受体(liver X receptor, LXR)是配体(激动剂)激活的转录因子。ERK1/2为重要激酶，在炎症、肿瘤、免疫等方面发挥重要功能。我们的工作发现LXR激动剂能强烈地诱导RAW.7细胞、EL4细胞、小鼠各组织尤其是巨噬细胞和T细胞中IFNgamma的表达，更进一步地我们发现LXR激动剂能明显地抑制移植肺肿瘤和化疗药诱导的肺原位癌的生长，降低肿瘤的发病率和致死率。然而上述各效果并不能在IFNgamma敲除小鼠中发生。这些结果表明LXR激动剂主要是通过诱导IFNgamma来发挥抗肿瘤作用；同时我们发现抑制ERK1/2通路具有与激活LXR通路类似的功能，即诱导IFNgamma表达、抑制肿瘤生长，降低肿瘤的发病率和致死率。我们的研究揭示了LXR通路新的生物功能，被认为是研究LXR从代谢到癌症的关键，为防治肿瘤提供新策略和理论支持。