Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis
Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis
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DOI：
10.1038/s41388-020-01540-4
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发表时间：
2020-11-11
期刊：
影响因子：
8
通讯作者：
Meloche, Sylvain
中科院分区：
文献类型：
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作者：
Girondel, Charlotte;Levesque, Kim;Meloche, Sylvain
白细胞介素 17 受体 D (IL-17RD) 也称为 Fgf 基因相似表达 (SEF)，被认为可作为信号中枢，负向调节有丝分裂信号通路（如 ERK1/2 MAP 激酶通路）和先天免疫信号通路。 IL-17RD的表达在某些实体瘤中下调，这导致了其可能发挥肿瘤抑制功能的假设。然而，IL-17RD 在肿瘤生物学中的作用仍有待体内研究。在这里，我们发现 Il17rd 的基因破坏导致衰老小鼠的多个组织中自发性肿瘤的形成增加。 IL-17RD 的缺失还会促进结肠炎相关结直肠癌模型中的肿瘤发展，并与炎症反应加剧相关。 IL-17RD 缺陷小鼠的结肠肿瘤的特征是炎症相关基因特征大量富集、促炎致瘤细胞因子（例如 IL-17A 和 IL-6）表达升高以及 STAT3 酪氨酸磷酸化增加。我们进一步表明，RNAi 耗竭 IL-17RD 可增强结肠腺癌细胞中的 Toll 样受体和 IL-17A 信号传导。 IL-17RD 基因灭活后，未观察到正常或肿瘤肠上皮细胞增殖的变化。我们的研究结果确立了 IL-17RD 作为小鼠肿瘤抑制因子，并表明该蛋白主要通过限制炎症的程度和持续时间来发挥其功能。
Interleukin-17 receptor D (IL-17RD), also known as similar expression to Fgf genes (SEF), is proposed to act as a signaling hub that negatively regulates mitogenic signaling pathways, like the ERK1/2 MAP kinase pathway, and innate immune signaling. The expression of IL-17RD is downregulated in certain solid tumors, which has led to the hypothesis that it may exert tumor suppressor functions. However, the role of IL-17RD in tumor biology remains to be studied in vivo. Here, we show that genetic disruption of Il17rd leads to the increased formation of spontaneous tumors in multiple tissues of aging mice. Loss of IL-17RD also promotes tumor development in a model of colitis-associated colorectal cancer, associated with an exacerbated inflammatory response. Colon tumors from IL-17RD-deficient mice are characterized by a strong enrichment in inflammation-related gene signatures, elevated expression of pro-inflammatory tumorigenic cytokines, such as IL-17A and IL-6, and increased STAT3 tyrosine phosphorylation. We further show that RNAi depletion of IL-17RD enhances Toll-like receptor and IL-17A signaling in colon adenocarcinoma cells. No change in the proliferation of normal or tumor intestinal epithelial cells was observed upon genetic inactivation of IL-17RD. Our findings establish IL-17RD as a tumor suppressor in mice and suggest that the protein exerts its function mainly by limiting the extent and duration of inflammation.