Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver

Abstract

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region was demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identified the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrated that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation was detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduced nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.

Ploidy dynamics increase the risk of liver cancer initiation

“…In mouse models, when ploidy is manipulated, increasingly polyploid livers develop fewer HCC and diploid hepatocytes are more at risk of LOH [4][5][6][7] . However, recently Matsumoto et al 11 and Lin et al 12 demonstrate the importance of ploidy dynamics in the formation of HCC in mice without directly manipulating hepatocyte ploidy.…”

“…Complete loss of all functional copies of a tumour suppressor gene may impose dysregulated proliferation and tumourigenic potential. Matsumoto et al 11 and Lin et al 12 suggest that particularly for liver cancer dynamic changes in ploidy, first polyploidisation then ploidy reduction of cells containing heterozygote loss of a tumour suppressor gene is associated with tumour initiation. Hypothetically mis-segregation of mutant tumour suppressor genes may occur during the process of ploidy reduction leading to LOH.…”

“…Lin et al used a diethylnitrosamine (DEN)-induced carcinogenic model to investigate the role of polyploidisation during the transformation of hepatocytes into preneoplastic HCC lesions 12 . DEN is a widely used hepatotoxin and carcinogen, inducing HCC in rodents, albeit with debatable relevance to human HCC 13 .…”