The role of leukemia inhibitory factor in colorectal cancer

项目摘要 白血病抑制因子(LIF)是一种多功能细胞因子。我们之前的研究表明，LIF是一种 抑癌基因P53的直接靶基因，并介导P53在母体生殖中的作用 同时，LIF与P53形成负反馈环，抑制P53的抑瘤作用。 LIF在肿瘤发生中具有复杂的作用；已有报道LIF抑制或促进肿瘤的发生。 不同类型的癌症。新出现的证据，包括我们的，已经表明LIF经常 在结直肠癌(CRC)中过表达。此外，LIF的过度表达通常与不良相关 结直肠癌患者的预后。这些观察结果有力地表明了LIF在促进结直肠癌中的关键作用 肿瘤发生学。目前，LIF在结直肠肿瘤发生中的确切作用和机制尚不清楚。 已定义。结直肠肿瘤起始干细胞(TICs)在结直肠癌的发生、发展中起关键作用 以及对治疗的抗拒。消除抽搐作为结直肠癌的一种治疗策略已被积极试验。 我们最近的研究表明，LIF存在于肠道干细胞(ISC)的巢中，并且对于 维护ISC编号和功能。ISCs的致癌激活在ISCs的启动中起着关键作用 CRC。我们的初步研究进一步表明，LIF驱动结直肠的脂代谢重编程 TICS是LIF促进结直肠TIC数量和功能的重要机制。这些 研究结果提示我们假设LIF对结直肠TIC的数量和功能是必不可少的，这在 TURN促进结直肠肿瘤的发生。我们进一步假设，靶向LIF和LIF驱动 代谢重编程可以抑制大肠痉挛，抑制大肠肿瘤的发生。在这 建议的研究，我们将确定LIF在结直肠肿瘤发生和结直肠TIC数中的作用 并通过使用不同的鼠标模型来实现功能(目标1)。我们将确定是否增加结直肠 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促进结直肠肿瘤的发生。我们将调查LIF是否调节了这些水平和活动 大肠痉挛中参与脂质代谢的关键转录因子，包括P53，以驱动脂质 代谢重新编程(目标2A)。我们将进一步测试LIF驱动的代谢重新编程 可用于结直肠癌治疗(目标2B)。本研究的目的是阐明其作用和机制。 LIF在结直肠癌中的表达，并评估靶向LIF驱动的脂代谢重编程是否有效 消除抽搐和治疗伴有LIF过表达的结直肠癌的策略。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，并提供理论基础 为开发LIF过表达的结直肠癌新的治疗靶点和策略奠定了基础。

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.