白血病抑制因子（LIF）在直结肠癌中的功能研究

Tumor suppressor p53 and its signaling pathway play a crucial role in colorectal tumor progression and therapeutic resistance. Recently, we identified LIF as a novel p53 target gene, which demonstrates that LIF is an important component of the p53 pathway. Considering the critical role of the p53 pathway in cancer, our finding suggests a potential role of LIF in cancer. However, to date, the role of LIF in tumorigenesis is poorly understood. Our preliminary studies show that overexpression of LIF mRNA and protein was observed in a high percentage of colorectal cancer. Furthermore, LIF promotes proliferation of colorectal cancer cells in vitro and colorectal xenograft tumor growth in vivo. We further found that LIF functions as a novel negative regulator of p53 to down-regulate p53 protein levels and function, including apoptoisis, in colorectal cancer cells. These findings strongly suggest that LIF may promote colorectal tumor growth and therapeutic resistance through the down-regulation of p53 function. Our preliminary data further show that LIF can transcriptionally induce the expression of p53 negative regulators, e.g. 14-3-3 ζ and miR-504, in colorectal cancer cells, which suggests the possible mechanisms by which LIF negatively regulates p53. Our preliminary data also suggest that LIF expression can be induced by oncogene Myc and NF-kB, which could be important mechanisms for LIF overexpression in colorectal cancers. Therefore, in this proposed study, we plan to study the role and mechanism of LIF in colorectal tumorigenesis by following 3 specific aims. 1)We will investigate the potential role of LIF in promoting colorectal tumor growth and resistance to chemotherapy in mouse tumor models. Furthermore, we will investigate whether the negative regulation of p53 is a novel mechanism by which LIF promotes colorectal tumorigenesis and chemotherapeutic resistance. 2)We will investigate the mechanism by which LIF negatively regulates p53 levels and function. Specifically, we will test whether 14-3-3 ζ and miR-504 mediate the role of LIF in negative regulation of p53. 3) We will investigate the mechanism of LIF overexpression in colorectal cancer. We will test whether and how Myc and NF-kB transcriptionally up-regulate LIF in colorectal cancer cells. These proposed aims will provide clear evidence and molecular mechanism for the role of LIF in colorectal tumorigenesis, and furthermore, provide molecular mechanism for LIF overexpression in colorectal cancer. This study will greatly increase our understanding of the molecular mechanism for colorectal cancer, and provide LIF as a potential target for cancer therapy.

p53缺失在结直肠癌发生发展及其化疗耐受中发挥关键作用。我们最近研究发现白血病抑制因子（LIF）是一个新的p53负调控分子，但其在肿瘤发生中的作用尚不明确。我们前期研究发现:LIF在直结肠癌中表达显著升高；LIF过表达可促进结直肠癌细胞的增殖和对药物的耐受，并促进裸鼠肠道移植瘤的生长；LIF能在转录水平诱导p53负调控因子的表达，如14-3-3ζ和miR-504；LIF能被原癌基因Myc和NF-kB诱导表达。因此，我们拟研究LIF的如下生物学功能：1)LIF在小鼠肿瘤模型中促进结直肠癌演进和对化疗药物耐受的潜在作用；2)LIF负调控p53的作用机制，尤其须明确14-3-3ζ和miR-504是否参与该调控；3)LIF在结直肠癌中过表达的机制，明确Myc和NF-kB能否在转录水平上调LIF及其调控机制。本课题不仅有助于揭示结直肠癌发生发展的机制，也能为其早期诊断、有效治疗和预后判断提供新策略。