The Role of Polyploidy in the Liver and Its Implications for Cancer Therapy

The description of liver polyploidy dates back to the 1940s, but its functional roles are still largely unknown. Numerous observations and studies have suggested that liver polyploidy may participate in multiple biological processes, including regeneration, stress response, and cancer. However, little evidence has established direct causal links between polyploidy and the observed phenotypes, mainly due to the lack of appropriate tools to specifically manipulate ploidy levels without causing other permanent changes. Specifically, whether polyploidy promotes or inhibits cancer is still under debate. Inspired by a phenomenon we observed in somatically mutated mouse livers, where homozygous Apc deletions were more difficult to obtain due to hepatic polyploidy, we aimed to build inducible tools to manipulate liver ploidy levels in vivo and systematically study the role of polyploidy in liver cancer. By toggling the weaning time and levels of Anln or E2f8 genes to change liver ploidy levels, we found that liver tumorigenesis was inversely correlated with initial polyploidy levels, suggesting a tumor suppressive role for polyploidy. Moreover, the additional alleles in polyploid cells led to a reduced likelihood of loss of heterozygosity (LOH), which largely contributed to the tumor suppressive effect. These results revealed an important function of polyploidy in mammalian livers and also led us to seek related therapeutic strategies for treating liver cancer. Since hepatocyte polyploidization mainly occurs through cytokinesis failure, we hypothesized that inhibiting cytokinesis could be an effective strategy to suppress liver tumorigenesis while preserving normal liver function. Therefore, we inhibited cytokinesis via Anln knockdown in multiple models and found that liver tumor development was significantly suppressed but normal liver function and regeneration capacity were not impaired. These results suggest that cytokinesis inhibition via Anln knockdown is potentially a safe and efficacious strategy for suppressing liver cancer. Overall, we uncovered an important role of polyploidy in the liver and explored its potential applications in liver cancer therapy.