The role of HIF2alpha in colon carcinogenesis

 描述（由申请人提供）：炎症是结肠癌进展的重要组成部分。在散发性结直肠癌（CRC）以及结肠炎相关结肠癌（CAC）中观察到肿瘤炎症。然而，目前尚不清楚是否预先存在 在CAC中明显炎症或在散发性CRC中观察到的炎症在癌症进展中起独特或重叠的作用。缺氧是大多数实体瘤的显著特征，并通过激活转录因子缺氧诱导因子（HIF）1a和HIF 2a介导反应。HIF 1a和HIF 2a在调节肿瘤细胞代谢、营养摄取、血管生成反应、细胞存活和增殖中是必需的。最近，我们发现HIF 2a在炎症和肿瘤粘膜中迅速活化，并且在许多情况下先于组织缺氧。HIF 2a（而不是HIF 1a）的激活诱导上皮引起的炎症反应，这在结肠癌进展中起重要作用。炎症灶中的HIF 2a活化导致直接靶基因的不同子集的增加。促炎性HIF 2a反应导致骨髓源性抑制细胞（MDSC）的积累，其是肿瘤生长中的重要细胞。尽管我们的研究结果表明HIF 2a在炎症和结肠肿瘤进展之间的分子联系中起着核心作用，但有关结肠炎，CAC和CRC的潜在机制以及重叠和不同作用的细节仍不清楚。我们假设上皮HIF 2a的快速激活通过MDSC的募集和增强活性导致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粘膜中HIF 2a快速激活的机制。我们的数据表明在发炎粘膜中新的癌代谢物介导的HIF 2a信号传导的活化，并且这将在结肠癌衍生的细胞系、患者衍生的腺瘤类器官模型和散发性CRC和CAC的小鼠模型中进行测试（ii）表征导致促炎性HIF 2a应答的精确机制。我们已经确定myc相关锌指蛋白（MAZ）作为HIF 2a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HIF 2a信号转导中的确切机制和需求。(iii)了解HIF 2a促炎反应如何增加结肠癌的生长和进展。肿瘤炎症导致精氨酸介导的生长反应增加，并减弱抗癌免疫反应。上皮HIF 2a在MDSC的募集和功能中至关重要，MDSC是对肿瘤细胞的免疫豁免至关重要的主要免疫细胞。我们将了解上皮HIF 2a调节结肠肿瘤中MDSC反应的确切机制。总之，所提出的体内和体外研究将确定HIF 2a在结肠癌中的基本作用，并为通过靶向HIF 2a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.