Remote reprogramming of hepatic circadian transcriptome by breast cancer
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Hiroaki Hojo1,2, Sora Enya1,2, Miki Arai1,3, Yutaka Suzuki3, Takashi Nojiri4,5, Kenji Kangawa4, Shinsuke Koyama6 and Shinpei Kawaoka1,2
1Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan
2ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency (JST), Kyoto, Japan
3The University of Tokyo, Graduate School of Frontier Science, Kashiwa, Japan
4Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita, Japan
6Department of Statistical Modeling, Institute of Statistical Mathematics, Tokyo, Japan
Shinpei Kawaoka, email: email@example.com
Keywords: breast cancer, RNA-Seq, hepatic circadian transcriptome, hepatic oxidative stress, hepatic polyploidization
Received: December 22, 2016 Accepted: March 14, 2017 Published: April 06, 2017
Cancers adversely affect organismal physiology. To date, the genes within a patient responsible for systemically spreading cancer-induced physiological disruption remain elusive. To identify host genes responsible for transmitting disruptive, cancer-driven signals, we thoroughly analyzed the transcriptome of a suite of host organs from mice bearing 4T1 breast cancer, and discovered complexly rewired patterns of circadian gene expression in the liver. Our data revealed that 7 core clock transcription factors, represented by Rev-erba and Rorg, exhibited abnormal daily expression rhythm in the liver of 4T1-bearing mice. Accordingly, expression patterns of specific set of downstream circadian genes were compromised. Osgin1, a marker for oxidative stress, was an example. Specific downstream genes, including E2f8, a transcriptional repressor that controls cellular polyploidy, displayed a striking pattern of disruption, “day-night reversal.” Meanwhile, we found that the liver of 4T1-bearing mice suffered from increased oxidative stress. The tetraploid hepatocytes population was concomitantly increased in 4T1-bearing mice, which has not been previously appreciated as a cancer-induced phenotype. In summary, the current study provides a comprehensive characterization of the 4T1-affected hepatic circadian transcriptome that possibly underlies cancer-induced physiological alteration in the liver.
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