The role of HIF2alpha in colon carcinogenesis

 描述(申请人提供)：炎症是结肠癌进展过程中的一个重要组成部分。散发性结直肠癌(CRC)和结肠炎相关结肠癌(CAC)均可观察到肿瘤炎症。然而，目前还不清楚是否已经存在 在CAC中明显的炎症或在散发性CRC中观察到的炎症在癌症进展中起着独特或重叠的作用。低氧是大多数实体瘤的一个显著特征，通过激活转录因子、低氧诱导因子(HIF)1a和HIF2a来介导反应。HIF1a和HIF2a在调节肿瘤细胞代谢、营养摄取、血管生成反应、细胞存活和增殖中起重要作用。最近，我们发现HIF2A在炎症和肿瘤黏膜中被迅速激活，并且在许多情况下先于组织缺氧。HIF2a(但不是HIF1a)的激活诱导了上皮细胞引起的炎症反应，这在结肠癌的进展中起着重要的作用。炎症灶中HIF2A的激活导致不同的直接靶基因子集的增加。促炎症的HIF2A反应导致髓系抑制细胞(MDSC)的聚集，MDSC是肿瘤生长中的重要细胞。尽管我们的结果表明HIF2A在炎症和结肠癌进展之间的分子联系中发挥了核心作用，但关于其在结肠炎、CAC和CRC中的潜在机制和重叠和不同的作用的细节仍不清楚。我们推测，上皮性HIF2A的快速激活通过MDSCs的募集和活性增强，导致了在结肠癌进展中至关重要的促炎反应。我们的主要目标是：(I)确定导致炎症和肿瘤黏膜中HIF2A快速激活的机制。我们的数据表明，一种新的肿瘤代谢物介导的炎症粘膜中HIF2A信号的激活，这将在结肠癌来源的细胞系、患者来源的腺瘤器官模型和散发性CRC和CAC的小鼠模型中进行测试(Ii)表征导致促炎HIF2A反应的精确机制。我们已经确定myc相关的锌指蛋白(MAZ)是HIF2A诱导的促炎靶基因所必需的新因子。我们将进一步了解MAZ在HIF2A信号转导中的确切机制和要求。(Iii)了解HIF2A促炎反应如何促进结肠癌的生长和进展。肿瘤炎症导致细胞因子介导的生长反应增加，并减弱抗癌免疫反应。上皮性HIF2A在MDSCs的募集和功能中起关键作用，MDSCs是肿瘤细胞免疫豁免权的关键免疫细胞。我们将了解上皮性HIF2A调节结肠癌MDSC反应的确切机制。综上所述，所提出的体内和体外研究将确定HIF2A在结肠癌中的基本作用，并为通过靶向HIF2A寻求新的治疗策略奠定基础。

 DESCRIPTION (provided by applicant): Inflammation is an important component in the progression of colon cancer. Tumor inflammation is observed in sporadic colorectal cancer (CRC) as well as colitis-associated colon cancer (CAC). However, it is still unclear if preexisting inflammation that is evident in CAC or inflammation that is observed in sporadic CRC play unique or overlapping roles in cancer progression. Hypoxia is a noted feature in most solid tumors and mediates a response through activation of transcription factors, hypoxia-inducible factor (HIF)1a and HIF2a. HIF1a and HIF2a are essential in regulating tumor cell metabolism, nutrient uptake, angiogenic response, cell survival and proliferation. Recently we show that HIF2a is rapidly activated in inflamed and tumor mucosa and in many cases precedes tissue hypoxia. Activation of HIF2a (but not HIF1a) induces an epithelial-elicited inflammatory response, which plays an important role in colon cancer progression. HIF2a activation in inflamed foci leads to an increase in distinct subset of direct target genes. The pro-inflammatory HIF2a response leads to accumulation of myeloid-derived suppressor cells (MDSC), which are important cells in tumor growth. Although our results demonstrate a central role for HIF2a in the molecular link between inflammation and colon tumor progression, details regarding the underlying mechanisms and overlapping and distinct roles in colitis, CAC and CRC are still unclear. We hypothesize that rapid activation of epithelial HIF2a leads to a pro-inflammatory response critical in colon cancer progression through the recruitment and enhanced activity of MDSCs. Our major goals are: (i) identify mechanisms leading to rapid activation of HIF2a in inflamed and tumor mucosa. Our data suggest a novel oncometabolite-mediated activation of HIF2a signaling in inflamed mucosa and this will be tested in colon cancer-derived cell lines, patient-derived adenoma organoid models and mouse models of sporadic CRC and CAC (ii) Characterize precise mechanisms leading to a pro-inflammatory HIF2a response. We have identified myc-associated zinc finger protein (MAZ) as novel factor essential for HIF2a-induced pro-inflammatory target genes. We will further understand precise mechanisms and requirement of MAZ in HIF2a signaling. (iii) Understand how the HIF2a pro-inflammatory response increases colon cancer growth and progression. Tumor inflammation leads to increase in cytokine-mediated growth response and attenuates anticancer immune responses. Epithelial HIF2a is critical in the recruitment and function of MDSCs, a major immune cell critical for immune privilege of tumor cells. We will understand the precise mechanism by which epithelial HIF2a regulates MDSC response in colon tumors. Taken together, the proposed in vivo and in vitro studies will identify fundamental roles of HIF2a in the colon cancer and lay the foundation for pursuing new therapeutic strategies by targeting HIF2a.