Abstract
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+ MB’s. Evidence for a direct transcriptional role of MYC on the B7-H3 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.
Highlights
Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor [1], accounting for approximately 20% of all pediatric brain tumors
To verify if B7 family of immune checkpoint homolog 3 (B7-H3) could be considered a therapeutic target in MB, biopsy specimens obtained from human MB tissues were stained using a B7-H3 antibody
This study emphasizes the role that B7-H3 plays in the progression of MYC+ MB cells, including angiogenesis
Summary
Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor [1], accounting for approximately 20% of all pediatric brain tumors. Group 3 and 4 Myc+ MB tumors tend to have a worse prognosis than Myc- tumors, suggesting that Myc dysregulation leads to greater resistance to current treatment options [4]. Group 3 tumors tend to overexpress c-Myc (MYC), while Group 4 tumors tend to exhibit more frequent N-Myc dysregulation than MYC [4,5]. MYC+ MB tumors tend to metastasize more frequently than other MB tumors [6]. Despite the negative outcomes associated with MYC amplifications, microRNAs hold promise as anti-tumor agents. One such microRNA, miR-29, was shown to be downregulated due to high MYC expression in both leukemia and lymphoma cells [7,8]
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