Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Oncogene. 2012 Apr 12;31(15):1923-37. doi: 10.1038/onc.2011.379. Epub 2011 Aug 29.
Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma.
放射治疗仍然是许多癌症的标准治疗方法，包括恶性小儿脑肿瘤髓母细胞瘤。放射治疗会导致长期的副作用，而放射抗性则导致肿瘤复发。耐药性髓母细胞瘤细胞占据了血管周围的龛位。它们表达 Yes 相关蛋白 (YAP)，这是 Sonic hedgehog (Shh) 的一个靶标，在 Shh 驱动的髓母细胞瘤中显著升高。在这里，我们报告 YAP 加速肿瘤生长并赋予放射抗性，在放射后促进持续增殖。YAP 活性通过驱动胰岛素样生长因子 2 (IGF2) 的表达和 Akt 的激活，使细胞能够在未修复 DNA 的情况下进入有丝分裂，导致 ATM/Chk2 失活和细胞周期检查点的废除。我们的结果确立了 YAP 在对抗基于放射的治疗和驱动基因组不稳定性方面的核心作用，并表明 YAP/IGF2/Akt 轴是髓母细胞瘤的一个治疗靶点。
