NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells

Journal of Hematology & Oncology

Ying-Hao Shen¹  Jia-Bin Cai¹  Jian Zhou¹  Bo Hu¹  Guang-Yu Ding¹  Pei-Yao Fu¹  Jia Fan¹  Guo-Ming Shi¹  Hui-Chuan Sun¹  Cheng Huang¹  Xiao-Dong Zhu¹  Ming Kuang²  Yuan Ji³  Zhen Yang⁴ 

[1] Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University;Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University;Department of Pathology, Zhongshan Hospital, Fudan University;Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology;

关键词: Hepatocellular carcinoma;    NLRX1;    Epithelial-mesenchymal-transition;    Tumor suppressor;    Senescence;    Transition;   

DOI  :  10.1186/s13045-018-0573-9

来源: DOAJ

【 摘 要 】

Abstract Background This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. Methods Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. Results NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. Conclusions NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment.

【 授权许可】

Unknown