Research Papers:

Remote reprogramming of hepatic circadian transcriptome by breast cancer

Hiroaki Hojo, Sora Enya, Miki Arai, Yutaka Suzuki, Takashi Nojiri, Kenji Kangawa, Shinsuke Koyama and Shinpei Kawaoka _

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Oncotarget. 2017; 8:34128-34140. https://doi.org/10.18632/oncotarget.16699

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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

Correspondence to:

Shinpei Kawaoka, email: [email protected]

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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