PMID- 29482578 OWN - NLM STAT- MEDLINE DCOM- 20191022 LR - 20231105 IS - 1756-8722 (Electronic) IS - 1756-8722 (Linking) VI - 11 IP - 1 DP - 2018 Feb 26 TI - NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells. PG - 28 LID - 10.1186/s13045-018-0573-9 [doi] LID - 28 AB - 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 beta-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. FAU - Hu, Bo AU - Hu B AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Ding, Guang-Yu AU - Ding GY AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Fu, Pei-Yao AU - Fu PY AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Zhu, Xiao-Dong AU - Zhu XD AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Ji, Yuan AU - Ji Y AD - Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Shi, Guo-Ming AU - Shi GM AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Shen, Ying-Hao AU - Shen YH AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Cai, Jia-Bin AU - Cai JB AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Yang, Zhen AU - Yang Z AD - Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China. FAU - Zhou, Jian AU - Zhou J AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Fan, Jia AU - Fan J AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Sun, Hui-Chuan AU - Sun HC AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. FAU - Kuang, Ming AU - Kuang M AD - Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhong Shan Rd 2, Guangzhou, 510080, China. kuangm@mail.sysu.edu.cn. FAU - Huang, Cheng AU - Huang C AD - Department of Liver Surgery and Transplant, Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Rd, Shanghai, 200032, China. huang.cheng@zs-hospital.sh.cn. AD - Key Laboratory for Carcinogenesis and Cancer Invasion, Chinese Ministry of Education, Shanghai, China. huang.cheng@zs-hospital.sh.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180226 PL - England TA - J Hematol Oncol JT - Journal of hematology & oncology JID - 101468937 RN - 0 (Mitochondrial Proteins) RN - 0 (NLRX1 protein, human) RN - 0 (NLRX1 protein, mouse) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/diagnosis/genetics/metabolism/*pathology MH - Cell Line, Tumor MH - Cellular Senescence MH - *Epithelial-Mesenchymal Transition MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Liver Neoplasms/diagnosis/genetics/metabolism/*pathology MH - Male MH - Mice, Nude MH - Middle Aged MH - Mitochondrial Proteins/analysis/genetics/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Prognosis MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction PMC - PMC5828065 OTO - NOTNLM OT - Epithelial-mesenchymal-transition OT - Hepatocellular carcinoma OT - NLRX1 OT - Senescence OT - Transition OT - Tumor suppressor COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Approval for use of human subjects was obtained from the research ethics committee of Zhongshan Hospital. Informed consent was obtained from each subject. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/02/28 06:00 MHDA- 2019/10/23 06:00 PMCR- 2018/02/26 CRDT- 2018/02/28 06:00 PHST- 2017/12/27 00:00 [received] PHST- 2018/02/11 00:00 [accepted] PHST- 2018/02/28 06:00 [entrez] PHST- 2018/02/28 06:00 [pubmed] PHST- 2019/10/23 06:00 [medline] PHST- 2018/02/26 00:00 [pmc-release] AID - 10.1186/s13045-018-0573-9 [pii] AID - 573 [pii] AID - 10.1186/s13045-018-0573-9 [doi] PST - epublish SO - J Hematol Oncol. 2018 Feb 26;11(1):28. doi: 10.1186/s13045-018-0573-9.