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: 9081527
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081527
• 关键词: Accounting; Apoptosis; Cancer Cell Growth; Cells; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Down-Regulation; Feedback; Gene Targeting; Goals; Growth; HCT116 Cells; Human; Hypoxia; Hypoxia Inducible Factor; LIF gene; 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; TP53 gene; Testing; Transcriptional Regulation; Tumor Markers; Tumor Suppression; Xenograft procedure; angiogenesis; base; cancer cell; chemotherapeutic agent; colon tumorigenesis; knock-down; 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p53在肿瘤抑制中起着至关重要的作用。最近，我们将白血病抑制因子（LIF）确定为一种新型的p53靶基因。迄今为止，LIF在肿瘤发生中的作用知之甚少。我们以下初步数据强烈表明，LIF是p53的新型负调节剂，并且在结直肠癌中起着重要作用。 1）在我们检查的人类大肠癌中，LIF过表达。 2）LIF下调p53蛋白水平和结直肠癌细胞的功能，包括HCT116 p53+/+细胞。 3）LIF促进结直肠癌细胞的增殖， 以及异种移植结直肠肿瘤的生长和血管生成。我们假设LIF表达在促进结直肠癌的肿瘤发生和治疗性中起着重要作用，并且p53功能的下调是重要的基本机制。在这项拟议的研究中，1）除了HCT116 p53+/+细胞外，我们还将研究p53水平的下调和LIF的功能。 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通过在结直肠细胞中诱导特定的p53阴性调节剂来下调p53功能。为了检验这一假设，我们将研究内源性LIF蛋白是否调节结直肠细胞中这些p53阴性调节剂的表达。此外，我们将研究这些p53阴性调节剂在结直肠细胞中LIF对p53下调的下调中的作用和机制。 3）我们将确定LIF在促进异种移植结肠直肠肿瘤中生长，血管生成和治疗性抗性中的作用。此外，我们将检验以下假设：p53 by LIF是促进LIF对异种移植物结直肠肿瘤肿瘤发生作用的重要机制。 4）我们将进一步研究结直肠癌细胞和人类结肠癌样品中LIF过度表达的机制。这项拟议的研究的目的是了解结直肠癌中LIF的作用和分子机制。这项研究应大大增加我们对结直肠肿瘤发生的分子机制的理解。此外，还具有直接发展LIF为重要的肿瘤生物标志物和结直肠癌的治疗靶标。