MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114–amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP . Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor–bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC -associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

中文翻译：

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由 MYC 上游开放阅读框编码的肽与原肌球蛋白受体激酶 B 结合并促进小鼠胶质母细胞瘤的生长


MYC 通过多种机制促进肿瘤生长。在这里，我们表明，在人胶质母细胞瘤中，变体 MYC 转录本编码来自上游开放阅读框 （uORF） MPEP 的 114 个氨基酸肽，即 MYC 前体 mRNA 编码蛋白 （MPEP）。分泌的 MPEP 通过直接结合和激活原肌球蛋白受体激酶 B （TRKB） 促进患者来源的异种移植瘤在体内生长，独立于 MYC，从而诱导下游 AKT-mTOR 信号传导。通过基因消融靶向 MPEP 减少了患者来源的 4121 和 3691 胶质母细胞瘤干细胞的生长。MPEP 中和抗体与小分子 TRKB 抑制剂联合给药可减少患者来源的异种移植荷瘤小鼠的胶质母细胞瘤生长。MPEP 在外科胶质母细胞瘤标本中过表达预后不良，支持其临床相关性。总之，我们的结果表明，MYC 相关 uORF 的肿瘤特异性翻译促进胶质母细胞瘤的生长，表明胶质母细胞瘤的新治疗策略。