PMID- 37726723 OWN - NLM STAT- MEDLINE DCOM- 20230921 LR - 20231122 IS - 1423-0127 (Electronic) IS - 1021-7770 (Print) IS - 1021-7770 (Linking) VI - 30 IP - 1 DP - 2023 Sep 19 TI - LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis. PG - 80 LID - 10.1186/s12929-023-00973-9 [doi] LID - 80 AB - BACKGROUND: Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1. RESULTS: SLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion. CONCLUSION: These findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer. CI - (c) 2023. National Science Council of the Republic of China (Taiwan). FAU - Chen, Yi-Ling AU - Chen YL AD - Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. FAU - Liu, Yi-Nan AU - Liu YN AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. FAU - Lin, Yen-Ting AU - Lin YT AD - Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. AD - Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan. FAU - Tsai, Meng-Feng AU - Tsai MF AD - Department of Biomedical Sciences, Da-Yeh University, Changhua, Taiwan. FAU - Wu, Shang-Gin AU - Wu SG AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. AD - Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan. FAU - Chang, Tzu-Hua AU - Chang TH AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. FAU - Hsu, Chia-Lang AU - Hsu CL AD - Department of Medical Research, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan. FAU - Wu, Huey-Dong AU - Wu HD AD - Division of Respiratory Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan. FAU - Shih, Jin-Yuan AU - Shih JY AUID- ORCID: 0000-0002-2854-5067 AD - Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. jyshih@ntu.edu.tw. AD - Department of Internal Medicine, National Taiwan University Hospital, #7, Chung-Shan South Road, Taipei, 100, Taiwan. jyshih@ntu.edu.tw. LA - eng GR - MOST 107-2314-B-002-250-MY3/Ministry of Science and Technology, Taiwan/ GR - MOST 110-2314-B-002-266-MY3/Ministry of Science and Technology, Taiwan/ GR - NTUH 109-S4550/National Taiwan University Hospital/ GR - NTUH 110-S5104/National Taiwan University Hospital/ GR - NTUH 112-S0299/National Taiwan University Hospital/ PT - Journal Article DEP - 20230919 PL - England TA - J Biomed Sci JT - Journal of biomedical science JID - 9421567 RN - 0 (RNA, Long Noncoding) SB - IM MH - Animals MH - Mice MH - *RNA, Long Noncoding/genetics MH - In Situ Hybridization, Fluorescence MH - *Lung Neoplasms/genetics MH - Signal Transduction/genetics MH - Lung PMC - PMC10507979 OTO - NOTNLM OT - Cytoskeleton OT - Long non-coding RNA OT - Lung cancer OT - Metastasis OT - SLCO4A1-AS1 COIS- The authors declare that they have no competing interests. EDAT- 2023/09/20 00:43 MHDA- 2023/09/21 06:42 PMCR- 2023/09/19 CRDT- 2023/09/19 23:47 PHST- 2023/02/24 00:00 [received] PHST- 2023/09/05 00:00 [accepted] PHST- 2023/09/21 06:42 [medline] PHST- 2023/09/20 00:43 [pubmed] PHST- 2023/09/19 23:47 [entrez] PHST- 2023/09/19 00:00 [pmc-release] AID - 10.1186/s12929-023-00973-9 [pii] AID - 973 [pii] AID - 10.1186/s12929-023-00973-9 [doi] PST - epublish SO - J Biomed Sci. 2023 Sep 19;30(1):80. doi: 10.1186/s12929-023-00973-9.