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 is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces 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.
Highlights
Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver
To address how hepatocytes transform into HCC cells, HCC was induced with DEN, and liver tissues were examined histologically at the preneoplastic stage
Because the zonal distribution of hepatocytes has been proposed to be relevant to the pharmacokinetic of DEN26, we investigated whether the DEN-induced hyperpolyploid hepatocytes were zone-specific
Summary
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. Adult hepatocytes can trans-differentiate into biliary-like cells during liver cancer formation, and dedifferentiate into progenitor-like cells in p53-deficient mouse liver[8,9] The relevance of these models for human HCC is still a matter of debate. The occurrence of hyperpolyploidy at early stages of tumor formation is believed to increase genomic instability and to be a pivotal step during tumorigenesis[22,23,24] Hyperpolyploid giant cells, such as human ovarian, breast, colon, and prostate cancer cell lines, have been demonstrated to serve as a source of stemness and tumor heterogeneity through genomic reduction pathways[25]. Under treatment with diethylnitrosamine (DEN), a carcinogenic compound known to cause HCC, hepatocytes hyperpolyploidization is a crucial step for the transformation of hepatocytes into HCC cells
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