- Researchers investigated the effects of circadian disruption in a mouse model of lung cancer.
- They found that chronic jet lag disrupts the expression of clock genes and increases tumor burden.
- They also identified a mechanism involving heat shock factor 1 (HSF1) genes that potentially underlies the increased rate of tumor formation in chronically jet-lagged mice.
- The findings demonstrate that HSF1 is a potential therapeutic target for preventing cancer risk in individuals exposed to chronic circadian disruption, such as shift workers.
Biological clocks in almost every cell in the body regulate your sleep-wake pattern over the course of 24 hours.
This pattern is known as your circadian rhythm and is underpinned by a molecular feedback loop — the transcription-translation feedback loop — involving specific genes and their protein products.
Lifestyle factors, such as shift work and travel across time zones, may cause disruption of circadian rhythms.
Recently, a team of scientists at Scripps Institute and the University of Rochester Wilmot Cancer Institute discovered another piece of the puzzle — a potential genetic link between lung tumor growth and disrupted circadian rhythms.
The results of this study were published in Science Advances.
Health effects of circadian rhythm disruption
Besides being responsible for the well-known symptoms of jet lag, circadian rhythm disruption has also been linked to:
- obesity
- type 2 diabetes
- cardiovascular disease
- hypertension
Multiple studies in human and animal models have indicated that the circadian clock also plays a role in the genesis and progression of cancer.
It is important to note, however, that the carcinogenic potential of circadian disruption is still being debated.
In June 2019, a working group of the International Agency for Research on Cancer (IARC) classified night shift work as a probable human carcinogen.
Yet a 2021 review co-authored by biochemist and Nobel laureate Dr. Aziz Sancar concluded that “the jury is still out on whether circadian disruption can promote cancer in general” due to insufficient data.
Effects of chronic jet lag in mouse model of lung cancer
In this study, researchers used KrasG12D mice, a genetically engineered mouse model of non-small cell lung cancer.
To induce chronic jet lag in the test group, the researchers housed the mice under an altered light-dark scheme that mimicked the effects of rotating shift work or frequent eastbound transmeridian flights.
Control mice were housed in typical light conditions: 12-hour light and 12-hour darkness.
As expected, the researchers found that chronic jet lag disrupted the expression of genes that regulate the circadian rhythm (known as clock genes) in the lung, liver, and, to a lesser extent, the spleen.
The researchers observed a 68% increase in tumor burden in chronically jet-lagged K mice compared to control mice at 25 weeks following infection (20 weeks in the chronic jet lag group).
The higher tumor burden was due to an increase in the number of tumors rather than their size, indicating that in this model, chronic jet lag influences early events in tumor progression.
“While several studies have convincingly shown an association between shift work and breast cancer, a few studies suggest that this could also be the case for lung cancer, particularly for smokers,” Frederic Gachon, Ph.D., associate professor at the Institute of Molecular Bioscience of the University of Queensland, not involved in the study, told Medical News Today.
“Nevertheless, the mechanisms are still poorly understood.”
“This study proposes a new mechanism linking the perturbed rhythmic activation of the HSF1 [heat shock factor 1] pathway involved in regulating cell proliferation and the increased burden of lung tumors. This suggests that shift workers, particularly smokers, should implement behavioral or nutritional interventions and regular medical motoring.”
– Frederic Gachon, Ph.D., molecular biologist
Linking circadian disruption to lung cancer
Based on the findings of previous studies, the researchers hypothesized the c-MYC oncoprotein could be connected to the increased tumor burden in chronic jet lag. (The c-MYC oncoprotein is a regulator gene that dysregulates in many forms of human cancer.)
But the new study reported that “unexpectedly, chronic jet lag resulted in significantly reduced accumulation of c-MYC in KrasG12D-driven lung tumors.”
When the researchers analyzed the tumors and tumor-bearing lung tissue, they noticed that chronic jet lag increases the expression of heat shock factor 1 (HSF1) target genes.
“In this study, we showed that gene expression associated with elevated [body] temperature is increased in samples collected from animals exposed to circadian disruption,” Katja Lamia, Ph.D., associate professor of Molecular Medicine at Scripps Research, and lead study author, told MNT.
“And other [studies in] people have shown that those genes are associated with increased tumor formation in several types of cancer.”
“One implication that we are excited about is the potential to use non-invasive measurement of body temperature to monitor shift workers and identify those who may be at a particular risk for detrimental health impacts of circadian disruption.”
– Katja Lamia, Ph.D., lead author of the study
The researchers also found that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells, paving the way for potential preventive cancer therapy for individuals with frequently disturbed circadian rhythms.
Study limitations and next steps for research
When asked about the study’s limitations, Dr. Gachon pointed out:
“This is a mouse model of lung cancer that mimics a subtype of lung cancer. Nevertheless, it has been shown to present important similarity with the development of lung cancer in humans.”
He added that “the role of the inhibition of HSF1 on cancer cell proliferation has been only assessed in vitro. An in vivo experiment [w]ould have been great (if possible).”
According to Dr. Lamia, while the new study has shown the impact of circadian disruption on the expression of genes linked to elevated body temperature, the study “did not actually demonstrate either that body temperature is affected by circadian disruption or that those changes are required for the increased tumor burden that we observed in mice that were exposed to circadian disruption.”
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