The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China.
Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Cell Rep. 2021 Feb 2;34(5):108724. doi: 10.1016/j.celrep.2021.108724.
The signal adaptor MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. Far less is known about the specific effects of MyD88 signaling in myofibroblasts in CAC development. Here, we used a CAC mouse model in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient mice are resistant to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumorigenesis, as evidenced by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts attenuates intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increases the secretion of osteopontin (OPN), which promotes macrophage M2 polarization through binding to αβ and CD44, leading to activation of the STAT3/PPARγ pathway. Thus, MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis.
信号接头蛋白 MyD88 是 TLR 信号的重要组成部分，在肠道微生物组相互作用中发挥重要作用。然而，它在结肠炎相关癌症（CAC）中的作用仍存在争议。关于 MyD88 信号在 CAC 发展中的成纤维细胞中的具体作用知之甚少。在这里，我们使用了一种 CAC 小鼠模型，其中 MyD88 在成纤维细胞中被选择性耗竭。肌成纤维细胞中 MyD88 缺失的小鼠对氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的肿瘤发生具有抗性，这表现在肿瘤的数量和大小减少。肌成纤维细胞中 MyD88 的缺失可减轻急性 DSS 诱导的结肠炎后肠道上皮细胞（IEC）的增殖。此外，肌成纤维细胞中的 MyD88 信号增加了骨桥蛋白（OPN）的分泌，OPN 通过与 αβ 和 CD44 结合促进巨噬细胞 M2 极化，从而激活 STAT3/PPARγ 通路。因此，肌成纤维细胞中的 MyD88 信号对结直肠癌的发展至关重要，并为预防结肠炎相关癌变提供了有希望的治疗靶点。
