Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
Institute of Traditional Chinese Medicine and Stem Cell Research, School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Cancer Res. 2021 Jun 15;81(12):3174-3186. doi: 10.1158/0008-5472.CAN-20-3979. Epub 2021 Apr 16.
Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of , encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in -deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting and or (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC. SIGNIFICANCE: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK-p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.
肾细胞癌 (RCC) 主要起源于肾近端小管。有趣的是，迄今为止，破坏人类 RCC 样本中经常发生突变的基因，仅在小鼠模型中产生了源自其他肾小管部分的 RCC。这阻碍了我们对 RCC 发病机制的理解。在这里，我们表明，mTOR 信号通路在 RCC 样本中经常被激活，它可以从肾近端小管引发 RCC 的发生。在近端小管细胞中敲除编码 mTOR 抑制剂的 ，会导致多个癌前肾囊肿。mTOR 激活增加了 MEK1 的表达和 ERK 的激活，而 Mek1 的缺失或抑制则减少了 -缺陷小鼠的囊肿形成。mTOR 激活还增加了 MKK6 的表达和 p38MAPK 的激活，而 p38α 编码基因的缺失进一步增强了囊肿的形成，并导致具有明确的 RCC 特征的 RCC。从机制上讲， 缺失以 p38MAPK 依赖的方式诱导了 p53 和 p16 的表达，并且缺失 和 或 （编码 p16）增强了肾细胞癌的发生。因此，mTOR 激活与 p38MAPK-p53/p16 通路的失活相结合，从肾近端小管引发 RCC 的发生。此外，这项研究揭示了 mTOR 控制细胞增殖的先前未识别的机制，并表明 MEK-ERK 轴可能是治疗 RCC 的潜在靶点。意义：小鼠模型研究表明，mTOR 激活与 p38MAPK-p53/p16 轴的失活相结合，引发了模拟人类疾病的肾细胞癌，确定了 RCC 治疗的潜在治疗靶点。
