Abstract 1039: Disruption of circadian clockwork in in vivo reprogramming induced mouse kidney cancer and human Wilms tumor

Abstract

Abstract Most organisms have evolved intrinsic circadian clock to optimize their behavior and physiology for diurnal environmental changes. The circadian clock exists not only in the organismal level but also in the peripheral organs and cellular levels, and regulates the various physiological aspects. Among these regulation systems, the relationship between circadian clock and cancer has been enthusiastically investigated in this decade. However, the mechanistic link connecting circadian clock and cancer has not been fully understood. Recently, we have clarified that circadian clock is tightly connected with cellular differentiation using the in vitro mouse embryonic stem cells (ESCs) differentiation model, and in addition, misregulation of differentiation leads to the circadian clock disruption via highly expression of KPNA2 and suppression of CLOCK protein. On the other hand, it was revealed that altered dedifferentiation leads to cancer development using in vivo reprogramming mouse model. So we considered that the viewpoint of dysdifferentiation can help to provide significant pathophysiological implications for the relationship of circadian clock and cancer. Firstly, we established Rosa26:M2-rtTA TetO:OSKM ES cells carrying circadian rhythm reporter mPer2:luc, and generated chimeric mice. The chimeric mice were treated with doxycycline (Dox) for transient in vivo reprogramming. The Dox treatment induced Wilms tumor-like kidney tumors and we sectioned the kidney tumor for monitoring real time bioluminescence signals, and examined the RNA and protein expression profiles. Here, we showed that the circadian clock was disrupted in the Wilms tumor-like mouse kidney tumor tissues, while the control mouse kidney exhibited the obvious circadian bioluminescence oscillation. And the gene expression signature of the circadian clock development correlated gene set in the tumor was similar to the dysdifferentiation-mediated circadian clock disrupted cells. Moreover, the highly expressed KPNA2 and suppression of CLOCK protein were also observed in the mouse tumor cells. Next, we examined human Wilms tumor gene and protein expression profiles. Astonishingly, the transcriptional signature of the circadian clock development correlated genes was similar to the mouse kidney tumor induced by dedifferentiation. Furthermore, the protein expression patterns of KPNA2 and CLOCK coincided with them. These findings suggest that the severely dedifferentiated cancers may lose their circadian clocks and the mechanism is common with the suppression mechanism during differentiation coupled circadian clock development. Moreover, circadian clock functionality may reflect the etiology of cancer development including dedifferentiation. In future prospects, a new view point of the circadian clock may help to evaluate the type of cancer cells, and it leads to more improved therapeutic strategy. Citation Format: Munehiro Ohashi, Yasuhiro Umemura, Yoichi Minami, Hitomi Watanabe, Tomoko Tanaka, Tsuneharu Miki, Osamu Ukimura, Tatsuro Tajiri, Gen Kondoh, Yasuhiro Yamada, Kazuhiro Yagita. Disruption of circadian clockwork in in vivo reprogramming induced mouse kidney cancer and human Wilms tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1039. doi:10.1158/1538-7445.AM2017-1039