C/EBPα-dependent pre-neoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer

ABSTRACT

Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes; while hepatocellular carcinoma (HCC) is caused by the de-differentiation of hepatocytes into Cancer Stem Cells (CSCs). However, the mechanisms of aggressive HBL and mechanisms that cause de-differentiation of hepatocytes into CSCs are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of de-differentiation of hepatocytes into CSCs. In both cases of liver cancer, the de-phosphorylation of tumor suppressor protein, C/EBPα, at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that de-ph-C/EBPα creates pre-neoplastic foci with CSC that give rise to HCC and aggressive HBL. C/EBPα-dependent de-differentiation of hepatocytes into CSCs includes increased proliferation of hepatocytes followed by generation of multi-nucleated hepatocytes and subsequent appearance of hepatocytes with DLK1-positive intra-nuclear inclusions. We further isolated C/EBPα-dependent multi-nucleated hepatocytes and found that they possess characteristics of tumor initiating cells, including elevation of stem cell markers. C/EBPα-dependent CSCs are observed in patients with aggressive hepatoblastoma and in patients with a predisposition for liver cancer. Conclusion: The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include the conversion of the tumor suppressor C/EBPα into an oncogenic isoform which further creates pre-neoplastic foci where hepatocytes de-differentiate into cancer cells, giving rise to liver cancer. This article is protected by copyright. All rights reserved.

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