NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Xiaomin Ma,Yumin Qiu,Tao Li,Yanlin Sun,Dapeng Ma,Caiyu Sun,Zhenzhi Qin,Yunxue Zhao,Yueke Lin,Lihui Han,Lihui Zhu

doi:10.1038/s41419-020-2368-5

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with increased morbidity and mortality in recent years
We investigated the role of nucleotide binding oligomerization domain 2 (NOD2) in the pathogenesis of HCC and showed that NOD2 deficiency promoted hepatocarcinogenesis, while overexpression of NOD2 inhibited tumorigenesis and reversed resistance to chemotherapy, which indicated an anti-tumor effect of NOD2 on HCC
Because AMPK is located at the center of multiple established tumor suppressor networks including LKB1, TSC1–TSC2 complex and p53, it is recognized to play a pivotal role in cancer progression[3]

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with increased morbidity and mortality in recent years. The therapeutic strategy for HCC is quite limited due to the common presence of resistance to chemotherapy[1,2]. Because of the critical connection between adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway and multiple cancers related signaling including mammalian target of rapamycin complex 1 (mTORC1) pathway, AMPK pathway is recognized to play a pivotal role in cancer[3]. Deficiency of AMPK pathway is reported to contribute to the progression of cancer and resistance to chemotherapeutic drugs in multiple types of cancers[4,5,6]. We identified nucleotide binding oligomerization domain 2 (NOD2), an innate immune sensor, as an efficient direct regulator of AMPK pathway; and loss of its expression in cancer cells promoted HCC progression and resistance to chemotherapy

Methods

Results

Conclusion