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CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma
BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNF...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762882/ https://www.ncbi.nlm.nih.gov/pubmed/35039066 http://dx.doi.org/10.1186/s12943-021-01482-9 |
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author | Du, Jinpeng Lan, Tian Liao, Haotian Feng, Xuping Chen, Xing Liao, Wenwei Hou, Guimin Xu, Lin Feng, Qingbo Xie, Kunlin Liao, Mingheng Chen, Xiangzheng Huang, Jiwei Yuan, Kefei Zeng, Yong |
author_facet | Du, Jinpeng Lan, Tian Liao, Haotian Feng, Xuping Chen, Xing Liao, Wenwei Hou, Guimin Xu, Lin Feng, Qingbo Xie, Kunlin Liao, Mingheng Chen, Xiangzheng Huang, Jiwei Yuan, Kefei Zeng, Yong |
author_sort | Du, Jinpeng |
collection | PubMed |
description | BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor). RESULTS: cNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment. CONCLUSIONS: Our findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-021-01482-9. |
format | Online Article Text |
id | pubmed-8762882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-87628822022-01-18 CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma Du, Jinpeng Lan, Tian Liao, Haotian Feng, Xuping Chen, Xing Liao, Wenwei Hou, Guimin Xu, Lin Feng, Qingbo Xie, Kunlin Liao, Mingheng Chen, Xiangzheng Huang, Jiwei Yuan, Kefei Zeng, Yong Mol Cancer Research BACKGROUND: Considerable evidence shows that circular RNAs (circRNAs) play an important role in tumor development. However, their function in intrahepatic cholangiocarcinoma (ICC) metastasis and the underlying mechanisms are incompletely understood. METHODS: circNFIB (hsa_circ_0086376, termed as cNFIB hereafter) was identified in human ICC tissues through circRNAs sequencing. The biological role of cNFIB was determined in vitro and in vivo by gain or loss of functional experiments. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to analyze the interaction of cNFIB with dual specificity mitogen-activated protein kinase kinase1 (MEK1). Duolink in situ proximity ligation assay (PLA) and coimmunoprecipitation (co-IP) assay were used to investigate the effects of cNFIB on the interaction between MEK1 and mitogen-activated protein kinase 2 (ERK2). Finally, a series of in vitro and in vivo experiments were performed to explore the influences of cNFIB on the anti-tumor activity of trametinib (a MEK inhibitor). RESULTS: cNFIB was significantly down-regulated in human ICC tissues with postoperative metastases. The loss of cNFIB was highly associated with aggressive characteristics and predicted unfavorable prognosis in ICC patients. Functional studies revealed that cNFIB inhibited the proliferation and metastasis of ICC cells in vitro and in vivo. Mechanistically, cNFIB competitively interacted with MEK1, which induced the dissociation between MEK1 and ERK2, thereby resulting in the suppression of ERK signaling and tumor metastasis. Moreover, we found that ICC cells with high levels of cNFIB held the potential to delay the trametinib resistance. Consistently, in vivo and in vitro studies demonstrated that cotreatment with trametinib and lentivirus vector encoding cNFIB showed greater inhibitory effect than isolated trametinib treatment. CONCLUSIONS: Our findings identified that cNFIB played a key role in ICC growth and metastasis by regulating MEK1/ERK signaling. Given the efficacy of cNFIB modulation on ICC suppression and trametinib sensitivity, cNFIB appears to be a potential therapeutic molecule for ICC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-021-01482-9. BioMed Central 2022-01-17 /pmc/articles/PMC8762882/ /pubmed/35039066 http://dx.doi.org/10.1186/s12943-021-01482-9 Text en © The Author(s) 2022 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 Du, Jinpeng Lan, Tian Liao, Haotian Feng, Xuping Chen, Xing Liao, Wenwei Hou, Guimin Xu, Lin Feng, Qingbo Xie, Kunlin Liao, Mingheng Chen, Xiangzheng Huang, Jiwei Yuan, Kefei Zeng, Yong CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title | CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title_full | CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title_fullStr | CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title_full_unstemmed | CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title_short | CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma |
title_sort | circnfib inhibits tumor growth and metastasis through suppressing mek1/erk signaling in intrahepatic cholangiocarcinoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762882/ https://www.ncbi.nlm.nih.gov/pubmed/35039066 http://dx.doi.org/10.1186/s12943-021-01482-9 |
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