Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis
Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is...
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doaj-476e91cf89554cc686e016616abce20a2020-11-24T22:15:25ZengMDPI AGJournal of Clinical Medicine2077-03832019-08-0188115810.3390/jcm8081158jcm8081158Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and AngiogenesisIan J. Purvis0Janardhan Avilala1Maheedhara R. Guda2Sujatha Venkataraman3Rajeev Vibhakar4Andrew J. Tsung5Kiran K. Velpula6Swapna Asuthkar7Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USADepartments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USADepartments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USADepartment of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USADepartment of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USADepartments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USADepartments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USADepartments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USAMedulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC<sup>+</sup> MB’s. Evidence for a direct transcriptional role of MYC on the <i>B7-H3</i> gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.https://www.mdpi.com/2077-0383/8/8/1158medulloblastomaMYCB7-H3miR-29p-STAT1angiogenesis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ian J. Purvis Janardhan Avilala Maheedhara R. Guda Sujatha Venkataraman Rajeev Vibhakar Andrew J. Tsung Kiran K. Velpula Swapna Asuthkar |
spellingShingle |
Ian J. Purvis Janardhan Avilala Maheedhara R. Guda Sujatha Venkataraman Rajeev Vibhakar Andrew J. Tsung Kiran K. Velpula Swapna Asuthkar Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis Journal of Clinical Medicine medulloblastoma MYC B7-H3 miR-29 p-STAT1 angiogenesis |
author_facet |
Ian J. Purvis Janardhan Avilala Maheedhara R. Guda Sujatha Venkataraman Rajeev Vibhakar Andrew J. Tsung Kiran K. Velpula Swapna Asuthkar |
author_sort |
Ian J. Purvis |
title |
Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis |
title_short |
Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis |
title_full |
Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis |
title_fullStr |
Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis |
title_full_unstemmed |
Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis |
title_sort |
role of myc-mir-29-b7-h3 in medulloblastoma growth and angiogenesis |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2019-08-01 |
description |
Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC<sup>+</sup> MB’s. Evidence for a direct transcriptional role of MYC on the <i>B7-H3</i> gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs. |
topic |
medulloblastoma MYC B7-H3 miR-29 p-STAT1 angiogenesis |
url |
https://www.mdpi.com/2077-0383/8/8/1158 |
work_keys_str_mv |
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