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Remote reprogramming of hepatic circadian transcriptome by breast cancer
Hiroaki Hojo1,2, Sora Enya1,2, Miki Arai1,3
1Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan.
Abstract:
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.
Insights
Breast cancer disrupts the body's internal clock. This study identifies disrupted liver gene rhythms and increased oxidative stress in mice, revealing potential mechanisms for cancer-induced physiological changes.
Area of Science:
- Molecular Biology
- Cancer Biology
- Chronobiology
Background:
- Cancers cause systemic physiological disruptions.
- Genes responsible for transmitting cancer-induced signals are largely unknown.
- Understanding these genes is crucial for treating cancer-related complications.
Purpose of the Study:
- To identify host genes involved in transmitting cancer-driven physiological disruption.
- To analyze the hepatic transcriptome in mice with 4T1 breast cancer.
- To characterize cancer-induced alterations in circadian gene expression and liver physiology.
Main Methods:
- Transcriptome analysis of host organs in mice bearing 4T1 breast cancer.
- Detailed examination of circadian gene expression patterns in the liver.
- Assessment of oxidative stress markers and hepatocyte ploidy.
Main Results:
- Complex rewiring of circadian gene expression was observed in the liver.
- Seven core clock transcription factors showed abnormal daily rhythms.
- Increased oxidative stress and a higher tetraploid hepatocyte population were found in tumor-bearing mice.
- Specific genes, like E2f8, exhibited a "day-night reversal" in expression.
Conclusions:
- The study characterizes the 4T1-affected hepatic circadian transcriptome.
- Disrupted circadian rhythms in the liver may underlie cancer-induced physiological alterations.
- Increased oxidative stress and tetraploid hepatocytes are potential cancer-induced phenotypes.