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

LIF（一种新型 p53 负调节因子）在结直肠癌中的作用

• 批准号: 8919276
• 负责人: Wenwei Hu
• 金额: $ 29.12万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919276
• 关键词: Accounting; Apoptosis; Biological Markers; Cancer Cell Growth; Cells; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Down-Regulation; Feedback; Gene Targeting; Goals; Growth; HCT116 Cells; Human; Hypoxia; Hypoxia Inducible Factor; Mediating; Messenger RNA; MicroRNAs; Molecular; Mus; Normal tissue morphology; Pathway interactions; Phenotype; Play; Prevention; Protein p53; Proteins; Regulation; Role; Sampling; Small Interfering RNA; Solid Neoplasm; Testing; Transcriptional Regulation; Tumor Suppression; Xenograft procedure; angiogenesis; base; cancer cell; chemotherapeutic agent; colon tumorigenesis; leukemia inhibitory factor; novel; overexpression; p53 Signaling Pathway; response; therapeutic target; therapy resistant; tumor; tumor growth; tumor progression; tumorigenesis

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.

描述（由申请人提供）：肿瘤抑制因子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。迄今为止，LIF在肿瘤发生中的作用知之甚少。我们以下的初步数据有力地表明，LIF是一种新的p53负调控因子，并在结直肠癌中发挥重要作用。1)LIF在我们检查的高比例的人类结直肠癌中过表达。2)LIF下调结肠直肠癌细胞（包括HCT 116 p53+/+细胞）中的p53蛋白水平和功能。3)LIF促进结肠直肠癌细胞的增殖， 以及异种移植结肠直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肿瘤发生和治疗抗性中起重要作用，p53功能的下调是一个重要的潜在机制。在本研究中，1）我们将研究除HCT 116 p53+/+细胞外，LIF对结肠直肠细胞中p53水平和功能的下调。2)我们将确定LIF下调p53的机制。我们的初步研究强烈表明，LIF下调p53的功能，通过诱导特定的p53负调节大肠癌细胞。为了验证这一假设，我们将研究内源性LIF蛋白是否调节这些p53负调节因子在结直肠细胞中的表达。此外，我们将研究这些p53负调控因子在大肠癌细胞中介导LIF下调p53的作用和机制。3)我们将确定LIF在促进异种移植结直肠肿瘤的生长、血管生成和治疗抗性中的作用。此外，我们将测试的假设，下调p53的LIF是一个重要的机制，促进作用的LIF对异种移植结直肠肿瘤的肿瘤发生。4)我们将进一步研究结直肠癌细胞和人类结直肠癌样本中LIF过表达的机制。这项研究的目的是了解LIF在结直肠癌中的作用和分子机制。这项研究将大大增加我们对结直肠肿瘤发生的分子机制的理解;此外，有直接的潜力开发LIF作为一个重要的肿瘤生物标志物和结直肠癌的治疗靶点。