Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors
Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors
复制标题
体内重编程诱导的小鼠肾肿瘤中昼夜节律的破坏
DOI：
10.1111/gtc.12552
复制
发表时间：
2017
期刊：
影响因子：
2.1
通讯作者：
Yagita Kazuhiro
中科院分区：
文献类型：
--
作者：
Ohashi Munehiro;Umemura Yasuhiro;Koike Nobuya;Tsuchiya Yoshiki;Inada Yutaka;Watanabe Hitomi;Tanaka Tomoko;Minami Yoichi;Ukimura Osamu;Miki Tsuneharu;Tajiri Tatsuro;Kondoh Gen;Yamada Yasuhiro;Yagita Kazuhiro
生物钟，调节细胞生理学，如能量代谢，驻留在整个身体的每个细胞水平。近年来研究表明，细胞生物钟与细胞分化密切相关。此外，小鼠胚胎干细胞（ESC）中细胞分化的失调诱导了具有受损生物钟振荡的异常分化细胞，伴随着CLOCK蛋白的转录后抑制。在这里，我们表明，昼夜分子振荡在由部分体内重编程诱导的分化异常介导的小鼠肾肿瘤中被破坏，类似于Wilms肿瘤。尽管ClockmRNA表达，但肿瘤细胞中CLOCK蛋白的表达显著降低。我们还发现，在人肾母细胞瘤中观察到类似的CLOCK丢失，这表明昼夜节律分子时钟可能在分化不良介导的胚胎肿瘤（如肾母细胞瘤）中被破坏，类似于体内重编程诱导的小鼠肾肿瘤。这些结果支持了我们以前的报道，并可能通过细胞分化和昼夜节律钟之间的相关性为理解癌症的病理生理本质提供新的观点。
The circadian clock, which regulates cellular physiology, such as energy metabolism, resides in each cell level throughout the body. Recently, it has been elucidated that the cellular circadian clock is closely linked with cellular differentiation. Moreover, the misregulation of cellular differentiation in mouse embryonic stem cells (ESCs) induced abnormally differentiated cells with impaired circadian clock oscillation, concomitant with the post‐transcriptional suppression of CLOCK proteins. Here, we show that the circadian molecular oscillation is disrupted in dysdifferentiation‐mediated mouse kidney tumors induced by partial in vivo reprogramming, resembling Wilms tumors. The expression of CLOCK protein was dramatically reduced in the tumor cells despite theClockmRNA expression. We also showed that a similar loss of CLOCK was observed in human Wilms tumors, suggesting that the circadian molecular clockwork may be disrupted in dysdifferentiation‐mediated embryonal tumors such as Wilms tumors, similar to the in vivo reprogramming‐induced mouse kidney tumors. These results support our previous reports and may provide a novel viewpoint for understanding the pathophysiological nature of cancers through the correlation between cellular differentiation and circadian clock.