Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis
Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis
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DOI：
10.1038/s41388-019-0816-4
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发表时间：
2019-07-11
期刊：
影响因子：
8
通讯作者：
Cramer, Thorsten
中科院分区：
文献类型：
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作者：
Rohwer, Nadine;Jumpertz, Sandra;Cramer, Thorsten
低氧诱导转录因子HIF-1是一个很有前途的肿瘤治疗靶点。然而，肿瘤微环境细胞中HIF-1和HIF-1靶基因的条件性缺失可导致肿瘤生长加速，需要详细表征细胞背景以充分理解HIF-1在肿瘤发生中的作用。我们通过Hif 1a基因位点的谱系限制性缺失，剖析了HIF-1在肠道肿瘤发生中的细胞类型特异性功能。肠上皮细胞特异性Hif 1a缺失减少了Wnt/β-连环蛋白的激活、肿瘤特异性代谢和炎症，显著抑制了肿瘤生长。髓系细胞中Hif 1a的缺失降低了肿瘤相关巨噬细胞中成纤维细胞活化因子的表达，导致肿瘤相关成纤维细胞（TAF）丰度降低，并显著降低了肿瘤形成。有趣的是，缺氧只能稀疏地检测到，并且与HIF-1 α没有空间关联，这证明了缺氧独立性的重要性，即，非典型的，HIF-1稳定肠肿瘤发生，这是以前没有认识到的。这为HIF-1的调节增加了另一层复杂性，并表明缺氧和HIF-1 α稳定在癌症中可以解偶联。总的来说，我们的数据表明，HIF-1是肠道肿瘤形成的关键促肿瘤因子，控制上皮肿瘤区室和肿瘤微环境中的关键致癌程序。
The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/beta-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1 alpha, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1 alpha stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.