Macrophages in High Fat Diet Enhanced Colorectal Cancer: Regulation by miRNA-155

描述（由申请人提供）：大多数结直肠癌（crc）的发展在很大程度上受非遗传因素的影响，如高脂肪饮食（HFD）诱导的肥胖。将肥胖与结直肠癌风险联系起来的病理生理机制包括炎症过程；脂肪组织巨噬细胞（ATM¿s）是炎症的主要来源，然而，尚未对其在结直肠癌中的具体作用进行系统评估。有证据证实miRNA-155对M¿诱导的炎症具有调节作用；研究表明，miRNA-155直接抑制M¿s中的细胞因子信号传导1 （SOCS1）抑制因子，从而增加其炎症潜能。虽然miRNA-155可以正向调节M¿-诱导的炎症是明确的，但在HFD增强CRC中，其在调节ATM¿-诱导的炎症中的作用还存在根本的空白。长期目标是了解ATM¿s在HFD增强型结直肠癌中的作用，可以使用行为和/或医学治疗进行靶向治疗。这项特殊研究的目的是确定ATM¿s在炎症和HFD增强CRC的后续进展中的作用，并进一步评估这一过程是否受miRNA-155调节。核心假设是，在HFD增强的CRC中，ATM诱导的炎症调节是通过miRNA-155介导的。提出这项研究的基本原理是阐明肥胖和结直肠癌之间的联系将转化为更有效的预防/治疗方法。这一假设将通过追求两个具体目标来验证：1)确定ATM¿s在炎症和CRC后续进展中的作用；2)评价miRNA-155在大肠癌中调控ATM诱导炎症的作用。在第一个目标下，我们将比较三种不同饱和脂肪百分比（占总热量的6%、12%和24%）的HFDs（占总热量的40%）对AOM/DSS CRC小鼠模型中CRC进展的影响，并进一步研究CRC、脂肪组织炎症、M¿极化和miRNA-155表达之间的关系。此外，通过将ATM¿s从饲喂HFDs的小鼠过继转移到饲喂正常饮食（ND）的CRC小鼠，我们将直接确定ATM¿s在CRC进展中的作用。在第二个目标中，我们将验证miRNA-155在HFD增强CRC中M¿诱导的炎症调节中起关键作用的假设。为此，使用miRNA-155-/-小鼠和AOM/DSS启动CRC，我们将研究miRNA-155在ATM诱导的炎症和随后的肿瘤发生中的作用。此外，通过将ATM¿s从HFD miRNA-155-/-小鼠移入野生型CRC小鼠，我们将确定ATM¿s对CRC进展的影响是否通过miRNA-155介导。这项研究的创新之处在于对ATM在CRC中的作用的研究，以及miRNA-155对这些ATM的调控。拟议的研究是重要的，因为它解决了预防hfd增强的CRC的发病率和进展。如果这一假设是正确的，miRNA-155可能是hfd增强CRC中ATM诱导炎症的重要治疗靶点。

DESCRIPTION (provided by applicant): The development of the majority of colorectal cancers (CRCs) is largely influenced by non-genetic factors such as high fat diet (HFD)-induced obesity. The pathophysiological mechanisms that link obesity to CRC risk include inflammatory processes; adipose tissue macrophages (ATM¿s) are a primary source of inflammation, however, there has been no systematic evaluation of their specific role in CRC. There is evidence to confirm a regulatory role of miRNA-155 on M¿-induced inflammation; it has been shown that miRNA-155 directly inhibits suppressor of cytokine signaling 1 (SOCS1) in M¿s, thus increasing their inflammatory potential. While it is clear that miRNA-155 can positively regulate M¿-induced inflammation, there is a fundamental gap in the understanding of its role on the regulation of ATM¿-induced inflammation in HFD enhanced CRC. The long- term goal is to understand the role of ATM¿s in HFD enhanced CRC that could be targeted using behavioral and or medical treatments. The objective of this particular investigation is to determine the role of ATM¿s on inflammation and subsequent progression of HFD enhanced CRC, and further, to evaluate if this process is regulated by miRNA-155. The central hypothesis is that the regulation of ATM¿-induced inflammation in HFD- enhanced CRC is mediated through miRNA-155. The rationale for the proposed research is that elucidating the link between obesity and CRC will translate to a more effective prevention/treatment approach. This hypothesis will be tested by pursuing two specific aims: 1) Determine the role of ATM¿s on inflammation and subsequent progression of CRC; and 2) Evaluate the role of miRNA-155 on regulation of ATM¿-induced inflammation in CRC. Under the first aim we will compare the effects of three HFDs (40% of total calories) differing in the percentage of saturated fat (6%, 12% & 24% of total calories) on CRC progression in the AOM/DSS mouse model of CRC, and further, examine the association between CRC, adipose tissue inflammation, M¿ polarization, and expression of miRNA-155. Further, using adoptive transfer of ATM¿s from mice fed HFDs to CRC mice fed normal diets (ND) we will directly determine the role of ATM¿s on progression of CRC. In the second aim, we will test the hypothesis that miRNA-155 plays a critical role in the regulation of M¿-induced inflammation in HFD enhanced CRC. To this end, using a miRNA-155-/- mouse and AOM/DSS to initiate CRC we will examine the role of miRNA-155 on ATM¿-induced inflammation and subsequent tumorigenesis. Further, using adoptive transfer of ATM¿s from HFD miRNA-155-/- mice to wildtype CRC mice that will be fed a ND we will determine if the effects of ATM¿s on CRC progression are mediated through miRNA-155. The innovation of this investigation is anchored in the examination of the role of ATM¿s in CRC, and further, the regulation of these M¿s by miRNA-155. The proposed investigation is significant as it addresses prevention of incidence and progression of HFD-enhanced CRC. If this hypothesis is correct miRNA-155 may be an important therapeutic target of ATM¿-induced inflammation in HFD-enhanced CRC.