A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2024-10-02 DOI:10.1126/scitranslmed.adk9524

Fanying Li, Kailin Yang, Xinya Gao, Maolei Zhang, Danling Gu, Xujia Wu, Chenfei Lu, Qiulian Wu, Deobrat Dixit, Ryan C. Gimple, Yongping You, Stephen C. Mack, Yu Shi, Tiebang Kang, Sameer A. Agnihotri, Michael D. Taylor, Jeremy N. Rich, Nu Zhang, Xiuxing Wang

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引用次数: 0

Abstract

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.

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由 MYC 上游开放阅读框编码的肽与肌球蛋白受体激酶 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，我们发现，在人类胶质母细胞瘤中，变异的 MYC 转录本从上游开放阅读框（uORF）MPEP 编码一种 114 氨基酸的肽，即 MYC 前 mRNA 编码蛋白（MPEP）。分泌的 MPEP 通过直接结合和激活肌球蛋白受体激酶 B (TRKB)，诱导下游 AKT-mTOR 信号传导，促进患者体内异种移植肿瘤的生长，而不依赖于 MYC。通过基因消融来靶向MPEP，可减少源自患者的4121和3691胶质母细胞瘤干细胞的生长。将MPEP中和抗体与小分子TRKB抑制剂联合使用，可减少胶质母细胞瘤在患者来源异种移植肿瘤小鼠体内的生长。手术胶质母细胞瘤标本中 MPEP 的过表达预示着不良预后，这支持了 MPEP 的临床意义。总之，我们的研究结果表明，MYC相关uORF的肿瘤特异性翻译会促进胶质母细胞瘤的生长，这为胶质母细胞瘤的治疗提供了一种新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.