IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.
IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.
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IL25 通过上调转录因子 GLI1 增强小鼠结肠炎相关肿瘤的发生
DOI：
10.3389/fimmu.2022.837262
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发表时间：
2022
影响因子：
7.3
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Liu J;Qian B;Zhou L;Shen G;Tan Y;Liu S;Zhao Z;Shi J;Qi W;Zhou T;Yang X;Gao G;Yang Z
白介素25(IL17E/IL25)在结肠炎和肠道内稳态中起重要作用。然而，IL25在结直肠癌中的表达和生物学作用尚不清楚。在本研究中，我们发现在结直肠癌微环境中，IL25主要由肿瘤干细胞表达。IL25基因缺失抑制了AOM/DSS治疗小鼠肿瘤的形成和生长，延长了小鼠的生存时间。IL25可促进癌组织和癌细胞球体的形成，阻止化疗诱导的肿瘤细胞凋亡。在机制上，IL25通过激活Hedgehog信号通路上调干细胞基因LGR5、CD133和ABC转运蛋白。IL25抑制AMPK的磷酸化，促进GLI1积聚以维持肿瘤干细胞。此外，IL25的表达与转移性结直肠癌患者的生存不良有关。综上所述，我们的工作揭示了一种免疫相关的机制，该机制本质上赋予癌细胞干细胞特性。我们的结果首次证明，IL25作为一种新的有效的内源性Hedgehog途径激动剂，可能是结直肠癌重要的预后因素和治疗靶点。
Interleukin-25 (IL17E/IL25) plays a critical role in colitis and intestinal homeostasis. However, the expression and biological role of IL25 in colorectal cancer is not properly understood. In this study, we show that IL25 is mainly expressed by cancer stem cells in the colorectal cancer microenvironment. Genetic deletion of IL25 inhibited tumor formation and growth and prolonged survival in AOM/DSS-treated mice. IL25 stimulated cancer organoid and cancer cells sphere formation and prevented the tumor from chemotherapy-induced apoptosis. Mechanistically, IL25 upregulated stem cell genes LGR5, CD133, and ABC transporters via activating the Hedgehog signaling pathway. IL25 inhibited phosphorylation of AMPK and promoted GLI1 accumulation to maintain cancer stem cells. Moreover, IL25 expression was associated with poor survival in patients with metastatic colorectal cancer. Taken together, our work reveals an immune-associated mechanism that intrinsically confers cancer cell stemness properties. Our results first demonstrated that IL25, as a new potent endogenous Hedgehog pathway agonist, could be an important prognostic factor and therapeutic target for CRC.