UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC
C/EBP homologous protein (CHOP), also known as growth arrest and DNA damage-inducible protein 153 (GADD153), belongs to the CCAAT/enhancer-binding protein (C/EBP) family. CHOP expression is induced by unfolded protein response (UPR), and sustained CHOP activation acts as a pivotal trigger for ER str...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13034 |
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| author | Vahid Arabkari Afrin Sultana David Barua Mark Webber Terry Smith Ananya Gupta Sanjeev Gupta |
| author_facet | Vahid Arabkari Afrin Sultana David Barua Mark Webber Terry Smith Ananya Gupta Sanjeev Gupta |
| author_sort | Vahid Arabkari |
| collection | DOAJ |
| description | C/EBP homologous protein (CHOP), also known as growth arrest and DNA damage-inducible protein 153 (GADD153), belongs to the CCAAT/enhancer-binding protein (C/EBP) family. CHOP expression is induced by unfolded protein response (UPR), and sustained CHOP activation acts as a pivotal trigger for ER stress-induced apoptosis. MicroRNA-616 is located within an intron of the CHOP gene. However, the regulation of miR-616 expression during UPR and its function in breast cancer is not clearly understood. Here we show that the expression of miR-616 and CHOP (host gene of miR-616) is downregulated in human breast cancer. Both miR-5p/-3p arms of miR-616 are expressed with levels of the 5p arm higher than the 3p arm. During conditions of ER stress, the expression of miR-616-5p and miR-616-3p arms was concordantly increased primarily through the PERK pathway. Our results show that ectopic expression of miR-616 significantly suppressed cell proliferation and colony formation, whereas knockout of miR-616 increased it. We found that miR-616 represses c-MYC expression via binding sites located in its protein coding region. Furthermore, we show that miR-616 exerted growth inhibitory effects on cells by suppressing c-MYC expression. Our results establish a new role for the CHOP locus by providing evidence that miR-616 can inhibit cell proliferation by targeting c-MYC. In summary, our results suggest a dual function for the CHOP locus, where CHOP protein and miR-616 can cooperate to inhibit cancer progression. |
| first_indexed | 2024-03-10T23:22:29Z |
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| id | doaj.art-4a9f4601f42542ed89536307be056adc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:22:29Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4a9f4601f42542ed89536307be056adc2023-11-19T08:11:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171303410.3390/ijms241713034UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYCVahid Arabkari0Afrin Sultana1David Barua2Mark Webber3Terry Smith4Ananya Gupta5Sanjeev Gupta6Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, IrelandDiscipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, IrelandDiscipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, IrelandDiscipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, IrelandMolecular Diagnostic Research Group, College of Science, University of Galway, H91 TK33 Galway, IrelandDiscipline of Physiology, School of Medicine, University of Galway, H91 TK33 Galway, IrelandDiscipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91 TK33 Galway, IrelandC/EBP homologous protein (CHOP), also known as growth arrest and DNA damage-inducible protein 153 (GADD153), belongs to the CCAAT/enhancer-binding protein (C/EBP) family. CHOP expression is induced by unfolded protein response (UPR), and sustained CHOP activation acts as a pivotal trigger for ER stress-induced apoptosis. MicroRNA-616 is located within an intron of the CHOP gene. However, the regulation of miR-616 expression during UPR and its function in breast cancer is not clearly understood. Here we show that the expression of miR-616 and CHOP (host gene of miR-616) is downregulated in human breast cancer. Both miR-5p/-3p arms of miR-616 are expressed with levels of the 5p arm higher than the 3p arm. During conditions of ER stress, the expression of miR-616-5p and miR-616-3p arms was concordantly increased primarily through the PERK pathway. Our results show that ectopic expression of miR-616 significantly suppressed cell proliferation and colony formation, whereas knockout of miR-616 increased it. We found that miR-616 represses c-MYC expression via binding sites located in its protein coding region. Furthermore, we show that miR-616 exerted growth inhibitory effects on cells by suppressing c-MYC expression. Our results establish a new role for the CHOP locus by providing evidence that miR-616 can inhibit cell proliferation by targeting c-MYC. In summary, our results suggest a dual function for the CHOP locus, where CHOP protein and miR-616 can cooperate to inhibit cancer progression.https://www.mdpi.com/1422-0067/24/17/13034unfolded protein responseER stressmiR-616c-MYCbreast cancer |
| spellingShingle | Vahid Arabkari Afrin Sultana David Barua Mark Webber Terry Smith Ananya Gupta Sanjeev Gupta UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC International Journal of Molecular Sciences unfolded protein response ER stress miR-616 c-MYC breast cancer |
| title | UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC |
| title_full | UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC |
| title_fullStr | UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC |
| title_full_unstemmed | UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC |
| title_short | UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC |
| title_sort | upr induced mir 616 inhibits human breast cancer cell growth and migration by targeting c myc |
| topic | unfolded protein response ER stress miR-616 c-MYC breast cancer |
| url | https://www.mdpi.com/1422-0067/24/17/13034 |
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