The Role of LIF, a Novel Negative Regulator of p53, in Colorectal Cancer

描述(申请人提供)：肿瘤抑制基因P53在肿瘤抑制中起关键作用。最近，我们发现白血病抑制因子(LIF)是一种新的P53靶基因。到目前为止，LIF在肿瘤发生中的作用还知之甚少。我们的初步数据有力地表明，LIF是一种新的P53负调控因子，在结直肠癌中发挥着重要作用。1)在我们研究的人类结直肠癌中，LIF过表达的比例很高。2)LIF下调结直肠癌细胞，包括HCT116 P53+/+细胞的P53蛋白水平和功能。3)LIF促进结直肠癌细胞增殖， 以及异种移植大肠肿瘤的生长和血管生成。我们推测LIF过表达在促进结直肠癌的发生和耐药中起重要作用，而P53功能下调是一个重要的潜在机制。在这项拟议的研究中，1)我们将研究LIF对大肠癌细胞和HCT116 P53+/+细胞的P53水平和功能的下调作用。2)我们将确定LIF下调P53的机制。我们的初步研究有力地表明，LIF通过诱导结直肠细胞中特定的P53负调控因子下调P53的功能。为了验证这一假说，我们将研究内源性LIF蛋白是否调节这些P53负调控因子在结直肠细胞中的表达。此外，我们还将探讨这些P53负调控因子在LIF下调大肠细胞P53表达中的作用和机制。3)研究LIF在促进结直肠癌异种移植瘤生长、血管生成和耐药中的作用。此外，我们还将验证这一假设，即LIF下调P53的表达是LIF促进异种结直肠癌发生的重要机制。4)我们将进一步研究LIF在结直肠癌细胞和人结直肠癌标本中过表达的机制。本研究的目的是了解LIF在结直肠癌中的作用和分子机制。这项研究将极大地加深我们对结直肠癌发生的分子机制的了解；此外，LIF有可能成为一种重要的肿瘤生物标记物和结直肠癌的治疗靶点。

DESCRIPTION (provided by applicant): Tumor suppressor p53 plays a crucial role in tumor suppression. Recently, we identified leukemia inhibitory factor (LIF) as a novel p53 target gene. To date, the role of LIF in tumorigenesis is poorly understood. Our following preliminary data strongly suggest that LIF is a novel negative regulator of p53 and plays an important role in colorectal cancer. 1) LIF is overexpressed in a high percentage of human colorectal cancers that we examined. 2) LIF down-regulates p53 protein levels and function in colorectal cancer cells, including HCT116 p53+/+ cells. 3) LIF promotes the proliferation of colorectal cancer cells, and the growth and angiogenesis of xenograft colorectal tumors. We hypothesize that LIF overexpression plays an important role in promoting tumorigenesis and therapeutic resistance in colorectal cancers, and the down-regulation of p53 function is an important underlying mechanism. In this proposed study, 1) we will investigate the down- regulation of p53 levels and function by LIF in colorectal cells in addition to HCT116 p53+/+ cells. 2) We will determine the mechanisms by which LIF down-regulates p53. Our preliminary studies strongly suggest that LIF down-regulates p53 function through the induction of specific p53 negative regulators in colorectal cells. To test this hypothesis, we will investigate whether endogenous LIF protein regulates the expression of these p53 negative regulators in colorectal cells. Furthermore, we will investigate the role and mechanisms of these p53 negative regulators in mediating the down-regulation of p53 by LIF in colorectal cells. 3) We will determine the role of LIF in promoting the growth, angiogenesis and therapeutic resistance in xenograft colorectal tumors. Furthermore, we will test the hypothesis that the down-regulation of p53 by LIF is an important mechanism for the promoting effect of LIF on tumorigenesis in xenograft colorectal tumors. 4) We will further investigate the mechanism accounting for LIF overexpression in both colorectal cancer cells and human colorectal cancer samples. The goal of this proposed study is to understand the role and molecular mechanisms of LIF in colorectal cancer. This study should greatly increase our understanding of molecular mechanisms of colorectal tumorigenesis; and furthermore, have the direct potential to develop LIF as an important tumor biomarker and a therapeutic target for colorectal cancers.