Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-β1)-induced epithelial–mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-β1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer.
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This project was supported by the National Natural Science Foundation of China (grant number: 81372314), the National Key Project for Infectious Diseases of China (2012ZX10002012-004) and the Shanghai Natural Science Fund for Youth Scholars (12ZR1442300). The authors appreciate the instruction in writing of the manuscript provided by Professor Hong Tu and Assistant Professor Yu Gan (State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, China).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Zhang, Q., Zhang, B., Zhang, K. et al. Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system. Oncogene 35, 4122–4131 (2016). https://doi.org/10.1038/onc.2015.484
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