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LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets

BACKGROUND: Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanis...

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Autores principales: Guo, Rong, Su, Yonghui, Zhang, Qi, Xiu, Bingqiu, Huang, Sheng, Chi, Weiru, Zhang, Liyi, Li, Lun, Hou, Jianjing, Wang, Jia, Chen, Jiajian, Chi, Yayun, Xue, Jingyan, Wu, Jiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926633/
https://www.ncbi.nlm.nih.gov/pubmed/36782197
http://dx.doi.org/10.1186/s12967-023-03967-1
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author Guo, Rong
Su, Yonghui
Zhang, Qi
Xiu, Bingqiu
Huang, Sheng
Chi, Weiru
Zhang, Liyi
Li, Lun
Hou, Jianjing
Wang, Jia
Chen, Jiajian
Chi, Yayun
Xue, Jingyan
Wu, Jiong
author_facet Guo, Rong
Su, Yonghui
Zhang, Qi
Xiu, Bingqiu
Huang, Sheng
Chi, Weiru
Zhang, Liyi
Li, Lun
Hou, Jianjing
Wang, Jia
Chen, Jiajian
Chi, Yayun
Xue, Jingyan
Wu, Jiong
author_sort Guo, Rong
collection PubMed
description BACKGROUND: Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown. METHODS: The transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5′/3′ RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays. RESULTS: Here, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5′ ends stable expressing LacRNA, which is released into the cytoplasm, and long 3′ ends of nuclear-retained lncRNA. LINC00478_3′RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61–140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model. CONCLUSION: Therefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-03967-1.
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spelling pubmed-99266332023-02-15 LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets Guo, Rong Su, Yonghui Zhang, Qi Xiu, Bingqiu Huang, Sheng Chi, Weiru Zhang, Liyi Li, Lun Hou, Jianjing Wang, Jia Chen, Jiajian Chi, Yayun Xue, Jingyan Wu, Jiong J Transl Med Research BACKGROUND: Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown. METHODS: The transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5′/3′ RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays. RESULTS: Here, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5′ ends stable expressing LacRNA, which is released into the cytoplasm, and long 3′ ends of nuclear-retained lncRNA. LINC00478_3′RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61–140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model. CONCLUSION: Therefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-03967-1. BioMed Central 2023-02-13 /pmc/articles/PMC9926633/ /pubmed/36782197 http://dx.doi.org/10.1186/s12967-023-03967-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Guo, Rong
Su, Yonghui
Zhang, Qi
Xiu, Bingqiu
Huang, Sheng
Chi, Weiru
Zhang, Liyi
Li, Lun
Hou, Jianjing
Wang, Jia
Chen, Jiajian
Chi, Yayun
Xue, Jingyan
Wu, Jiong
LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title_full LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title_fullStr LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title_full_unstemmed LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title_short LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets
title_sort linc00478-derived novel cytoplasmic lncrna lacrna stabilizes phb2 and suppresses breast cancer metastasis via repressing myc targets
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926633/
https://www.ncbi.nlm.nih.gov/pubmed/36782197
http://dx.doi.org/10.1186/s12967-023-03967-1
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