The role of leukemia inhibitory factor in colorectal cancer

白血病抑制因子在结直肠癌中的作用

• 批准号: 10549746
• 负责人: Wenwei Hu
• 金额: $ 36.89万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549746
• 关键词: ApcMin/+ mice; Azoxymethane; CD36 gene; CDX2 gene; Cancer Etiology; Cell Count; Cell physiology; Cells; Cessation of life; Clinical; Colon; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Complex; Data; Development; Epithelium; Fatty Acids; Feedback; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; In Vitro; Internal Ribosome Entry Site; Intestines; Knock-in Mouse; Knock-out; Knockout Mice; LGR5 gene; LIF gene; LIFR gene; Lipids; LoxP-flanked allele; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Mus; Oncogenic; Pathologic Processes; Pathway interactions; Physiological Processes; Play; Prognosis; Reporting; Reproduction; Role; Sampling; Signal Transduction; TP53 gene; Testing; Therapeutic; Time; Tissues; Tumor Promotion; Tumor Suppression; Tumor Suppressor Genes; Work; anti-cancer; base; cancer cell; cancer initiation; cancer type; chemical carcinogen; colon cancer patients; colon tumorigenesis; colorectal cancer treatment; cytokine; enhancing factor; gene repression; in vivo; leukemia inhibitory factor receptor; lipid metabolism; mouse model; neutralizing antibody; new therapeutic target; overexpression; oxidation; small molecule inhibitor; stem cell niche; stem cells; stem-like cell; stemness; targeted treatment; therapy resistant; transcription factor; tumor; tumor initiation; tumorigenesis; uptake

Project Summary Leukemia inhibitory factor (LIF) is a multi-functional cytokine. Our previous studies reveal that LIF is a direct target gene of tumor suppressor p53 and mediates the function of p53 in maternal reproduction, and at the same time, LIF forms a negative feedback loop with p53 to inhibit p53 function in tumor suppression. LIF has a complex role in tumorigenesis; LIF has been reported to suppress or promote tumorigenesis in different types of cancers. Emerging evidence, including ours, has shown that LIF is frequently overexpressed in colorectal cancer (CRC). Further, LIF overexpression is often associated with poor prognosis in CRC patients. These observations strongly suggest a critical role of LIF in promoting colorectal tumorigenesis. Currently, the precise role and mechanism of LIF in colorectal tumorigenesis are poorly defined. Colorectal tumor-initiating stem-like cells (TICs) play a critical role in CRC initiation, progression and resistance to therapy. Eliminating TICs has been actively tested as a therapeutic strategy for CRC. Our recent study shows that LIF is present in the intestinal stem cells (ISC) niche and is essential to maintain ISC number and functions. Oncogenic activation in ISCs plays a critical role in the initiation of CRC. Our preliminary studies further suggest that LIF drives lipid metabolic reprogramming of colorectal TICs as an important mechanism whereby LIF promotes colorectal TIC number and functions. These findings prompt us to hypothesize that LIF is essential for colorectal TIC number and functions, which in turn promotes colorectal tumorigenesis. We further hypothesize that targeting LIF and LIF-driven metabolic reprogramming can suppress colorectal TICs and inhibit colorectal tumorigenesis. In this proposed study, we will determine the role of LIF in colorectal tumorigenesis and colorectal TIC number and functions by using different mouse models (Aim 1). We will determine whether increasing colorectal TIC number and functions through LIF-driven lipid metabolic reprograming is a critical mechanism whereby LIF promotes colorectal tumorigenesis. We will investigate whether LIF regulates the levels and activities of critical transcription factors involved in lipid metabolism in colorectal TICs, including p53, to drive lipid metabolic reprogramming (Aim 2A). We will further test whether the LIF-driven metabolic reprogramming can be targeted for CRC therapy (Aim 2B). The goal of this study is to elucidate the role and mechanism of LIF in CRC, and assess whether targeting LIF-driven lipid metabolic reprogramming is an effective strategy to eliminate TICs and treat CRC with LIF overexpression. If accomplished successfully, this study will establish the critical role of LIF in CRC, reveal its underlying mechanisms, and provide the rationale and base for the development of new therapeutic targets and strategies for CRC with LIF overexpression.

项目摘要 白血病抑制因子（LIF）是多功能细胞因子。我们以前的研究表明，LIF是 肿瘤抑制p53的直接靶基因，并介导p53在母体繁殖中的功能，并介导 同时，LIF形成具有p53的负反馈回路，以抑制肿瘤抑制中的p53功能。 LIF在肿瘤发生中具有复杂的作用。据报道，LIF抑制或促进肿瘤发生 不同类型的癌症。包括我们在内的新兴证据表明，LIF经常是 过表达结直肠癌（CRC）。此外，LIF过表达通常与较差有关 CRC患者的预后。这些观察结果强烈表明LIF在促进结直肠癌中的关键作用 肿瘤发生。目前，LIF在结直肠肿瘤发生中的确切作用和机制差 定义。结直肠肿瘤发射干细胞（TICS）在CRC启动，进展中起关键作用 和对治疗的抵抗力。消除抽搐已被积极测试，作为CRC的治疗策略。 我们最近的研究表明，LIF存在于肠道干细胞（ISC）生态位，对于 维护ISC号和功能。 ISC中的致癌激活在开始中起着至关重要的作用 CRC。我们的初步研究进一步表明，LIF驱动着结直肠的脂质代谢重编程 TIC是LIF促进结直肠曲目的数量和功能的重要机制。这些 调查结果促使我们假设LIF对于结直肠探针的数字和功能至关重要， 转弯促进结直肠肿瘤发生。我们进一步假设针对LIF和LIF驱动 代谢重编程可以抑制结直肠性抽搐并抑制结直肠肿瘤发生。在这个 拟议的研究，我们将确定LIF在结直肠肿瘤发生和结直肠肿瘤中的作用 通过使用不同的鼠标模型（AIM 1）来函数。我们将确定是否增加结直肠癌 通过LIF驱动的脂质代谢重编程的TIC数量和功能是一种关键机制 LIF促进结直肠肿瘤发生。我们将调查LIF是否调节水平和活动 脂质直肠抽搐中脂质代谢涉及的关键转录因子（包括p53）驱动脂质 代谢重编程（AIM 2A）。我们将进一步测试LIF驱动的代谢重编程是否 可以针对CRC治疗（AIM 2B）。这项研究的目的是阐明角色和机制 CRC中的LIF，并评估靶向LIF驱动的脂质代谢重编程是否有效 消除抽动和使用LIF过度表达的CRC的策略。如果成功完成，这项研究 将确定LIF在CRC中的关键作用，揭示其潜在机制，并提供理由 以及开发具有LIF过表达的CRC的新治疗靶标和策略的基础。