Yuan Qi, Zhang Jie, Liu Yu, Chen Haiqiang, Liu Haiyang, Wang Jinyan, Niu Meng, Hou Lingling, Wu Zhenlong, Chen Zhinan, Zhang Jinhua
The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, PR China.
Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, PR China.
J Pathol. 2022 Apr;256(4):414-426. doi: 10.1002/path.5856. Epub 2022 Jan 27.
Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). MyD88 controls the expression of several key modifier genes in liver tumorigenesis; however, whether and how MyD88 in myofibroblasts contributes to the development of fibrosis-associated liver cancer remains elusive. Here, we used an established hepatocarcinogenesis mouse model involving apparent liver fibrogenesis in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient (Fib-MyD88 KO) mice developed significantly fewer and smaller liver tumor nodules. MyD88 deficiency in myofibroblasts attenuated liver fibrosis and aerobic glycolysis in hepatocellular carcinoma tissues. Mechanistically, MyD88 signaling in myofibroblasts increased the secretion of CCL20, which promoted aerobic glycolysis in cancer cells. This process was dependent on the CCR6 receptor and ERK/PKM2 signaling. Furthermore, liver tumor growth was greatly relieved when the mice were treated with a CCR6 inhibitor. Our data revealed a critical role for MyD88 in myofibroblasts in the promotion of hepatocellular carcinoma by affecting aerobic glycolysis in cancer cells and might provide a potential molecular therapeutic target for HCC. © 2021 The Pathological Society of Great Britain and Ireland.
肝星状细胞（HSCs）和癌症相关成纤维细胞（CAFs）在肝纤维化和肝细胞癌（HCC）中起关键作用。MyD88控制肝脏肿瘤发生中几个关键修饰基因的表达；然而，肌成纤维细胞中的MyD88是否以及如何促进纤维化相关肝癌的发展仍不清楚。在这里，我们使用了一个已建立的肝癌发生小鼠模型，该模型涉及明显的肝纤维化，其中MyD88在肌成纤维细胞中被选择性敲除。肌成纤维细胞MyD88缺陷（Fib-MyD88 KO）小鼠形成的肝脏肿瘤结节明显更少、更小。肌成纤维细胞中MyD88的缺乏减轻了肝细胞癌组织中的肝纤维化和有氧糖酵解。机制上，肌成纤维细胞中的MyD88信号增加了CCL20的分泌，从而促进癌细胞的有氧糖酵解。这个过程依赖于CCR6受体和ERK/PKM2信号。此外，用CCR6抑制剂治疗小鼠时，肝脏肿瘤生长得到显著缓解。我们的数据揭示了肌成纤维细胞中的MyD88通过影响癌细胞的有氧糖酵解在促进肝细胞癌方面的关键作用，并可能为肝癌提供一个潜在的分子治疗靶点。© 2021英国和爱尔兰病理学会。
