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.
Highlights
Cancer is a disease that affects host physiology at multiple levels, worsening quality of life and in certain cases causes organismal death
Through extensively investigating the effects of 4T1 breast cancer on hepatic gene expression, we revealed that 4T1 disrupted daily expression patterns of 7 core clock transcription factors and a number of downstream circadian genes
The liver and lung, the two major targets of 4T1 metastasis [19,20,21], kidney, and heart were chosen for RNA-seq analyses. 4T1-bearing or sham-operated mice were sacrificed at 3 and 7 days post-transplantation, when the extent of 4T1-induced inflammation measured by quantitative reverse transcription PCR (qRT-PCR) against an inflammation marker S100a8 was relatively mild (Supplementary Figure 1A)
Summary
Cancer is a disease that affects host physiology at multiple levels, worsening quality of life and in certain cases causes organismal death. Such physiological disruption includes multi-organ chronic inflammation, insulin resistance, metabolic disorder, cachexia, and so on [1, 2]. Mechanisms underlying these cancermediated physiological alterations and their physiological significance are still poorly understood. It remains enigmatic how these physiological disturbances are related to each other. Most importantly, mitigating cancer-induced adverse effects on host physiology, if possible, may provide patients a way to live with cancer while maintaining a relatively high quality of life
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