A study in mice finds that physical activity reduces the likelihood of the disease developing and explains why.

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Exercising may reduce the risk of liver cancer, a new study in mice suggests.

Liver cancer is on the rise, having more than tripled since 1980, according to the American Cancer Society (ACS).

This increase corresponds to the time frame of the “diabesity” pandemic, which refers to the close association between obesity and type 2 diabetes.

As well as being increasingly common, liver cancer is often deadly, with the number of fatalities closely mirroring the number of diagnoses. Each year, the ACS note, 800,000 people around the world receive a liver cancer diagnosis, and the disease is responsible for about 700,000 deaths.

A new study in mice has shown that exercise may prevent the development of liver cancer. The researchers have also identified two chemical pathways behind the onset of the disease.

The study features in the Journal of Hepatology.

While liver cancer statistics for the United States are alarming — with experts predicting 42,810 diagnoses and 30,160 deaths in 2020 — the U.S. is not even among the top 25 countries for liver cancer. In 2018, the country with the most cases was Mongolia, with Egypt coming in second and Gambia third.

Males are more likely than females to develop liver cancer, and the condition is the fastest growing cause of cancer deaths in men in the U.S. The most common form of the disease is hepatocellular carcinoma, and this is the type of liver cancer that the new study investigates.

While exercise is often a recommended way to maintain a moderate weight and avoid or control type 2 diabetes, the study’s authors focused on identifying a mechanism directly linking activity level to liver cancer.

Geoffrey C. Farrell, from the Australian National University Medical School at The Canberra Hospital, Garran, is the lead investigator of the study. He comments on the significance of the study, saying:

“Some population data suggest that persons who exercise regularly are less likely to develop liver cancer, but studies addressing whether this has a real biological basis and, if so, identifying the molecular mechanism that produces such a protective effect are few, and the findings have been inconclusive.”

Farrell and his colleagues genetically modified mice to increase their appetites, causing them to develop obesity and diabetes as young adults. The team also injected the mice with a low dose of a cancer-causing agent before dividing them into two groups.

One group of mice had access to an exercise wheel, on which they ran as far as 40 kilometers per week. The other group had no opportunity to engage in physical activity and quickly developed obesity. As a result of their artificially increased appetites, even the active mice had obesity by the time 6 months had passed.

By the end of the trial, the inactive mice had fatty liver disease, a precursor of liver cancer, while the other group did not.

The mice in both groups had obesity and were candidates for diabetes. However, far more of the sedentary mice — 64% compared with 15% — developed liver cancer.

Having established a link between exercise and liver health, the researchers embarked on an investigation of the chemical processes at play. They identified two molecular pathways as the connecting mechanisms.

The first was the stress-activated protein kinase JNK1. Research has implicated JNK1 in tumor development, although its precise role is still under investigation. The authors of the current study found that exercise switched it off.

Conversely, the study demonstrated that exercise activated a tumor suppressor gene called p53. With scientists referring to it as a “guardian of the genome” and “policemen of the oncogenes,” p53 seems to regulate p27, a cell cycle inhibitor that can halt the out-of-control cancerous growth of cells.

The study’s results provide two reasons for hope when it comes to combatting liver cancer.

First is the beneficial role of exercise in preventing the disease.

“Exercise has already been shown to improve some outcomes for patients with cirrhosis,” says Farrell. “If the present studies in an animal model that closely resembles humans with fatty liver disease can be replicated in patients, it is likely that exercise could delay onset of liver cancer and mitigate its severity, if not completely prevent it — thereby greatly improving patient outcomes.”

The identification of the related molecular pathways is equally encouraging.

Farrell notes that it “points to ways that drugs or pharmaconutrients could be employed to harness the powerful protective effect of exercise to lower risk of liver cancer in [people with overweight and] diabetes.”