NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway
NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway
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NOD2通过靶向AMPK通路抑制肿瘤发生并增加肝细胞癌的化疗敏感性。
DOI：
10.1038/s41419-020-2368-5
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发表时间：
2020-03-06
影响因子：
9
通讯作者：
Han, Lihui
中科院分区：
文献类型：
--
作者：
Ma, Xiaomin;Qiu, Yumin;Han, Lihui
核苷酸结合寡聚化结构域2（Nucleotide binding oligomerization domain 2，NOD 2）是公认的先天性免疫传感器，能够启动针对病原体的有效免疫应答。许多先天性免疫传感器已被报道在肿瘤发生中具有重要意义。然而，NOD 2在癌症中的作用还不清楚。在这里，我们研究了NOD 2在肝细胞癌（HCC）的发展中的作用。我们在N-亚硝基二乙胺（DEN）/四氯化碳（CCl 4）诱导的肝癌小鼠模型和异种移植瘤模型中证明NOD 2缺陷促进肝癌的发生。体外研究表明，NOD 2具有抑癌作用，抑制肝癌细胞的增殖、集落形成和侵袭。临床研究表明，在临床肝癌组织中NOD 2表达完全缺失或显著下调，且NOD 2表达缺失与疾病的晚期阶段显著相关。进一步的研究表明，NOD 2通过激活5 '-磷酸腺苷（AMP）激活的蛋白激酶（AMPK）信号通路发挥抗肿瘤作用，NOD 2通过激活AMPK通路诱导细胞凋亡，显著增强肝癌细胞对索拉非尼、乐伐替尼和5-FU的敏感性。此外，我们证明NOD 2通过直接与AMPK α-LKB 1复合物结合激活AMPK通路，导致自噬介导的HCC细胞凋亡。总之，本研究表明NOD 2通过直接激活AMPK通路在肝癌细胞中发挥抑癌和化疗调节的作用，提示通过上调NOD 2-AMPK信号轴治疗肝癌是一种潜在的治疗策略。
Nucleotide binding oligomerization domain 2 (NOD2) is a recognized innate immune sensor which can initiate potent immune response against pathogens. Many innate immune sensors have been reported to be of great importance in carcinogenesis. However, the role of NOD2 in cancer is not well understood. Here we investigated the role of NOD2 in the development of hepatocellular carcinoma (HCC). We demonstrated that NOD2 deficiency promoted hepatocarcinogenesis in N-nitrosodiethylamine (DEN)/carbon tetrachloride (CCl4) induced HCC mice model and xenograft tumor model. In vitro investigation showed that NOD2 acted as a tumor suppressor and inhibited proliferation, colony formation and invasion of HCC cells. Clinical investigation showed that NOD2 expression was completely lost or significantly downregulated in clinical HCC tissues, and loss of NOD2 expression was significantly correlated with advanced disease stages. Further investigation showed that NOD2 exerted its anti-tumor effect through activating adenosine 5 '-monophosphate (AMP) -activated protein kinase (AMPK) signaling pathway, and NOD2 significantly enhanced the sensitivity of HCC cells to sorafenib, lenvatinib and 5-FU treatment through activating AMPK pathway induced apoptosis. Moreover, we demonstrated that NOD2 activated AMPK pathway by directly binding with AMPK alpha-LKB1 complex, which led to autophagy-mediated apoptosis of HCC cells. Altogether, this study showed that NOD2 acted as a tumor suppressor as well as a chemotherapeutic regulator in HCC cells by directly activating AMPK pathway, which indicated a potential therapeutic strategy for HCC treatment by upregulating NOD2-AMPK signaling axis.