PMID- 30839115 OWN - NLM STAT- MEDLINE DCOM- 20200622 LR - 20211204 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 70 IP - 1 DP - 2019 Jul TI - Metabolism-induced tumor activator 1 (MITA1), an Energy Stress-Inducible Long Noncoding RNA, Promotes Hepatocellular Carcinoma Metastasis. PG - 215-230 LID - 10.1002/hep.30602 [doi] AB - Metastasis is the main cause of cancer-related death, yet the underlying mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as crucial regulators of malignancies; however, their functions in tumor metastasis remain largely unexplored. In this study, we identify a lncRNA, termed metabolism-induced tumor activator 1 (MITA1), which is up-regulated in hepatocellular carcinoma (HCC) and contributes to metastasis. MITA1, a chromatin-enriched lncRNA discovered by our nuclear RNA sequencing, is significantly induced by energy stress. This induction of MITA1 is governed by the liver kinase B1-adenosine monophosphate-activated protein kinase (LKB1-AMPK) pathway and DNA methylation. Knockdown of MITA1 dramatically inhibits the migration and invasion of liver cancer cells in vitro and HCC metastasis in vivo. Mechanistically, MITA1 promotes the epithelial-mesenchymal transition, an early and central step of metastasis, which may partly attribute to an increase in Slug (snail family zinc finger 2) transcription. MITA1 deficiency reduces the expression of the mesenchymal cell markers, especially Slug, whereas Slug overexpression greatly impairs the effects of MITA1 deficiency on HCC migration and invasion. Correspondingly, there is a positive correlation between the levels of MITA1 and Slug precursors in HCC tissues. Conclusion: Our data reveal MITA1 as a crucial driver of HCC metastasis, and highlight the identified AMPK-MITA1-Slug axis as a potential therapeutic strategy for HCC. CI - (c) 2019 by the American Association for the Study of Liver Diseases. FAU - Ma, Meilin AU - Ma M AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Xu, Haixia AU - Xu H AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Liu, Geng AU - Liu G AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Wu, Jing AU - Wu J AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Li, Chunhua AU - Li C AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Wang, Xiuxuan AU - Wang X AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Zhang, Sifan AU - Zhang S AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Xu, Heng AU - Xu H AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Ju, Shenggen AU - Ju S AD - College of Computer Science, Sichuan University, Chengdu, China. FAU - Cheng, Wei AU - Cheng W AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Dai, Lunzhi AU - Dai L AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Wei, Yuquan AU - Wei Y AD - State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Tian, Yan AU - Tian Y AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. FAU - Fu, Xianghui AU - Fu X AD - Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China. LA - eng GR - 2018ZX09201018-005/Ministry of Science and Technology of the People's Republic of China/International GR - 81441121/National Natural Science Foundation of China/International GR - 81502631/National Natural Science Foundation of China/International GR - 81570527/National Natural Science Foundation of China/International GR - 81802836/National Natural Science Foundation of China/International GR - 91540113/National Natural Science Foundation of China/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190426 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (RNA, Long Noncoding) RN - 0 (SNAI1 protein, human) RN - 0 (Snail Family Transcription Factors) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (STK11 protein, human) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 2.7.4.3 (Adenylate Kinase) SB - IM MH - A549 Cells MH - AMP-Activated Protein Kinase Kinases MH - Adenylate Kinase/metabolism MH - Carcinoma, Hepatocellular/*metabolism MH - DNA Methylation MH - Energy Metabolism MH - *Epithelial-Mesenchymal Transition MH - Hep G2 Cells MH - Humans MH - Liver Neoplasms/*metabolism MH - *Neoplasm Metastasis MH - Protein Serine-Threonine Kinases/metabolism MH - RNA, Long Noncoding/*metabolism MH - Snail Family Transcription Factors/metabolism EDAT- 2019/03/07 06:00 MHDA- 2020/06/23 06:00 CRDT- 2019/03/07 06:00 PHST- 2018/11/22 00:00 [received] PHST- 2019/02/28 00:00 [accepted] PHST- 2019/03/07 06:00 [pubmed] PHST- 2020/06/23 06:00 [medline] PHST- 2019/03/07 06:00 [entrez] AID - 10.1002/hep.30602 [doi] PST - ppublish SO - Hepatology. 2019 Jul;70(1):215-230. doi: 10.1002/hep.30602. Epub 2019 Apr 26.