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Pharmacological inhibition of IRAK1 attenuates colitis-induced tumorigenesis in mice by inhibiting the inflammatory response and epithelial–mesenchymal transition
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2021-07-17 , DOI: 10.1002/jbt.22838
Zeyu Feng 1, 2 , Zhenglan Duan 1, 2 , Guoping Shi 2 , Qiong Wang 3 , Jinyong Zhou 3 , Yugen Chen 1
Affiliation  

Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial–mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial–mesenchymal transition.

中文翻译:

IRAK1 的药理抑制通过抑制炎症反应和上皮间质转化来减弱小鼠结肠炎诱导的肿瘤发生

结直肠癌 (CRC) 是第三大最常见的癌症类型。在这里,我们使用结肠炎诱导的肿瘤发生小鼠模型研究了 IRAK1 和 IRAK4 作为预防策略的抑制作用。CRC 临床数据来自基因表达综合数据库 (GEO)。通过在 C57BL/6 小鼠中用氧化偶氮甲烷 (AOM) 和葡聚糖硫酸钠 (DSS) 处理来诱导实验性炎症依赖性 CRC 模型。通过腹膜内注射以 3 mg/kg 每周两次对小鼠施用 IRAK1/4 抑制剂,持续 9 周。IRAK1/4 抑制剂减弱了组织学变化并阻止了肿瘤生长。肿瘤相关蛋白,包括 p65 和 Ki-67,在 AOM/DSS 治疗的小鼠中被 IRAK1/4 抑制剂下调。此外,IRAK1/4 抑制剂给药有效地降低了炎性细胞因子的表达。此外,我们观察到 IRAK1/4 抑制剂治疗通过抑制上皮 - 间质转化来减弱结肠炎诱导的肿瘤发生。这些观察结果表明,抑制 IRAK1 和 IRAK4 可能通过抑制炎症反应和上皮间质转化来抑制实验性结肠炎诱导的肿瘤发生。
更新日期:2021-09-15
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