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NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-03-06 , DOI: 10.1038/s41419-020-2368-5 Xiaomin Ma 1 , Yumin Qiu 1 , Yanlin Sun 2 , Lihui Zhu 1 , Yunxue Zhao 3 , Tao Li 4 , Yueke Lin 1 , Dapeng Ma 1 , Zhenzhi Qin 1 , Caiyu Sun 1 , Lihui Han 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-03-06 , DOI: 10.1038/s41419-020-2368-5 Xiaomin Ma 1 , Yumin Qiu 1 , Yanlin Sun 2 , Lihui Zhu 1 , Yunxue Zhao 3 , Tao Li 4 , Yueke Lin 1 , Dapeng Ma 1 , Zhenzhi Qin 1 , Caiyu Sun 1 , Lihui Han 1
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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 AMPKα-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.
中文翻译：
NOD2通过靶向AMPK途径抑制肝癌的发生并增加对肝细胞癌的化学敏感性。
核苷酸结合寡聚结构域2（NOD2）是公认的先天免疫传感器，可以启动针对病原体的有效免疫反应。据报道，许多先天免疫传感器在致癌作用中非常重要。但是，NOD2在癌症中的作用尚不十分清楚。在这里，我们研究了NOD2在肝细胞癌（HCC）发生中的作用。我们证明NOD2缺乏促进N-亚硝基二乙胺（DEN）/四氯化碳（CCl4）诱导的HCC小鼠模型和异种移植肿瘤模型中的肝癌发生。体外研究表明，NOD2起到抑癌作用，并抑制HCC细胞的增殖，集落形成和侵袭。临床研究表明，临床肝癌组织中NOD2表达完全丧失或明显下调，NOD2表达的丧失与疾病的晚期阶段显着相关。进一步的研究表明，NOD2通过激活5'-单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）信号通路发挥其抗肿瘤作用，并且NOD2通过以下方式显着增强了HCC细胞对索拉非尼，lenvatinib和5-FU治疗的敏感性激活AMPK途径诱导的细胞凋亡。此外，我们证明了NOD2通过直接与AMPKα-LKB1复合物结合而激活了AMPK途径，从而导致自噬介导的HCC细胞凋亡。总之，这项研究表明，NOD2通过直接激活AMPK途径在HCC细胞中起着抑癌和化学治疗的调节作用，这表明通过上调NOD2-AMPK信号传导轴可以为HCC治疗提供潜在的治疗策略。
更新日期：2020-03-06
中文翻译：
NOD2通过靶向AMPK途径抑制肝癌的发生并增加对肝细胞癌的化学敏感性。
核苷酸结合寡聚结构域2（NOD2）是公认的先天免疫传感器，可以启动针对病原体的有效免疫反应。据报道，许多先天免疫传感器在致癌作用中非常重要。但是，NOD2在癌症中的作用尚不十分清楚。在这里，我们研究了NOD2在肝细胞癌（HCC）发生中的作用。我们证明NOD2缺乏促进N-亚硝基二乙胺（DEN）/四氯化碳（CCl4）诱导的HCC小鼠模型和异种移植肿瘤模型中的肝癌发生。体外研究表明，NOD2起到抑癌作用，并抑制HCC细胞的增殖，集落形成和侵袭。临床研究表明，临床肝癌组织中NOD2表达完全丧失或明显下调，NOD2表达的丧失与疾病的晚期阶段显着相关。进一步的研究表明，NOD2通过激活5'-单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）信号通路发挥其抗肿瘤作用，并且NOD2通过以下方式显着增强了HCC细胞对索拉非尼，lenvatinib和5-FU治疗的敏感性激活AMPK途径诱导的细胞凋亡。此外，我们证明了NOD2通过直接与AMPKα-LKB1复合物结合而激活了AMPK途径，从而导致自噬介导的HCC细胞凋亡。总之，这项研究表明，NOD2通过直接激活AMPK途径在HCC细胞中起着抑癌和化学治疗的调节作用，这表明通过上调NOD2-AMPK信号传导轴可以为HCC治疗提供潜在的治疗策略。
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