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TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling
BACKGROUND: Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resista...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291992/ https://www.ncbi.nlm.nih.gov/pubmed/30541550 http://dx.doi.org/10.1186/s12943-018-0922-x |
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author | Hou, Zhenlin Guo, Kaixuan Sun, Xuling Hu, Fuqing Chen, Qianzhi Luo, Xuelai Wang, Guihua Hu, Junbo Sun, Li |
author_facet | Hou, Zhenlin Guo, Kaixuan Sun, Xuling Hu, Fuqing Chen, Qianzhi Luo, Xuelai Wang, Guihua Hu, Junbo Sun, Li |
author_sort | Hou, Zhenlin |
collection | PubMed |
description | BACKGROUND: Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear. METHODS: The expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated β-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms. RESULTS: We found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression. CONCLUSION: These data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-018-0922-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6291992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62919922018-12-17 TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling Hou, Zhenlin Guo, Kaixuan Sun, Xuling Hu, Fuqing Chen, Qianzhi Luo, Xuelai Wang, Guihua Hu, Junbo Sun, Li Mol Cancer Research BACKGROUND: Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear. METHODS: The expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated β-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms. RESULTS: We found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression. CONCLUSION: These data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-018-0922-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-12-12 /pmc/articles/PMC6291992/ /pubmed/30541550 http://dx.doi.org/10.1186/s12943-018-0922-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Hou, Zhenlin Guo, Kaixuan Sun, Xuling Hu, Fuqing Chen, Qianzhi Luo, Xuelai Wang, Guihua Hu, Junbo Sun, Li TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title | TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title_full | TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title_fullStr | TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title_full_unstemmed | TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title_short | TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling |
title_sort | trib2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through ap4/p21 signaling |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291992/ https://www.ncbi.nlm.nih.gov/pubmed/30541550 http://dx.doi.org/10.1186/s12943-018-0922-x |
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