PMID- 33243974 OWN - NLM STAT- MEDLINE DCOM- 20211013 LR - 20211013 IS - 2059-3635 (Electronic) IS - 2095-9907 (Print) IS - 2059-3635 (Linking) VI - 5 IP - 1 DP - 2020 Nov 27 TI - Identification of miR-515-3p and its targets, vimentin and MMP3, as a key regulatory mechanism in esophageal cancer metastasis: functional and clinical significance. PG - 271 LID - 10.1038/s41392-020-00275-8 [doi] LID - 271 AB - Metastasis is the main factor of treatment failure in cancer patients, but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed. This study aims to explore novel key metastasis-related microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC). By comparing miRNA profiles of the highly metastatic ESCC cell sublines, we established through serial in vivo selection with the parental cells, we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues, further decreased in metastatic tumors, and moreover, markedly associated with advanced stage, metastasis and patient survival. The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers, and more importantly, suppress invasion and metastasis of ESCC cells. Mechanistically, we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3 (MMP3) expression by binding to the coding sequence and 3'untranslated region, respectively. In addition, the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues, which may lead to deregulation of miR-515-3p expression in ESCC. Furthermore, our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice. Taken together, this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC. FAU - Hu, Hui-Fang AU - Hu HF AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. FAU - Xu, Wen Wen AU - Xu WW AD - Guangdong Provincial Key Laboratory of Bioengineering Medicine and MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China. FAU - Zhang, Wei-Xia AU - Zhang WX AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. FAU - Yan, Xin AU - Yan X AUID- ORCID: 0000-0001-6248-3931 AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. FAU - Li, Yang-Jia AU - Li YJ AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. FAU - Li, Bin AU - Li B AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. libin2015@jnu.edu.cn. FAU - He, Qing-Yu AU - He QY AUID- ORCID: 0000-0003-0503-9492 AD - Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou, China. tqyhe@jnu.edu.cn. LA - eng GR - 31770888/National Natural Science Foundation of China (National Science Foundation of China)/International GR - 31570828/National Natural Science Foundation of China (National Science Foundation of China)/International GR - 81672953/National Natural Science Foundation of China (National Science Foundation of China)/International GR - 81803551/National Natural Science Foundation of China (National Science Foundation of China)/International GR - 81773085/National Natural Science Foundation of China (National Science Foundation of China)/International GR - 81973339/National Natural Science Foundation of China (National Science Foundation of China)/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201127 PL - England TA - Signal Transduct Target Ther JT - Signal transduction and targeted therapy JID - 101676423 RN - 0 (Biomarkers, Tumor) RN - 0 (MIRN515 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Neoplasm) RN - 0 (VIM protein, human) RN - 0 (Vimentin) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Biomarkers, Tumor/*biosynthesis MH - Cell Line, Tumor MH - Esophageal Neoplasms/genetics/*metabolism/pathology MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Matrix Metalloproteinase 3/*biosynthesis/genetics MH - MicroRNAs/*biosynthesis/genetics MH - Neoplasm Metastasis MH - Neoplasm Proteins/*biosynthesis/genetics MH - RNA, Neoplasm/*biosynthesis/genetics MH - Vimentin/*biosynthesis PMC - PMC7693265 COIS- The authors declare no competing interests. EDAT- 2020/11/28 06:00 MHDA- 2021/10/14 06:00 PMCR- 2020/11/27 CRDT- 2020/11/27 05:39 PHST- 2020/02/03 00:00 [received] PHST- 2020/07/28 00:00 [accepted] PHST- 2020/07/16 00:00 [revised] PHST- 2020/11/27 05:39 [entrez] PHST- 2020/11/28 06:00 [pubmed] PHST- 2021/10/14 06:00 [medline] PHST- 2020/11/27 00:00 [pmc-release] AID - 10.1038/s41392-020-00275-8 [pii] AID - 275 [pii] AID - 10.1038/s41392-020-00275-8 [doi] PST - epublish SO - Signal Transduct Target Ther. 2020 Nov 27;5(1):271. doi: 10.1038/s41392-020-00275-8.