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 dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (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 dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα‐dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta‐like 1 homolog–positive intranuclear inclusions. We further isolated C/EBPα‐dependent multinucleated hepatocytes and found that they possess characteristics of tumor‐initiating cells, including elevation of stem cell markers. C/EBPα‐dependent cancer stem cells are observed in patients with aggressive HBL 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 conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857‐1871).

中文翻译：

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C/EBPα 依赖性肿瘤前肿瘤灶是肝细胞癌和侵袭性小儿肝癌的起源

最近的出版物表明经典肝母细胞瘤（HBL）是肝干细胞未能分化为肝细胞的结果，而肝细胞癌（HCC）是由肝细胞去分化为癌症干细胞引起的。然而，侵袭性 HBL 的机制和导致肝细胞去分化为癌症干细胞的机制尚不清楚。我们发现，与 HCC 相似但与经典 HBL 相反，侵袭性 HBL 是肝细胞去分化为癌症干细胞的结果。在这两种肝癌病例中，肿瘤抑制蛋白 CCAAT/增强子结合蛋白 α (C/EBPα) 在 Ser193（人类蛋白质中的 Ser190）处的去磷酸化或 Ser193 突变为 Ala 导致具有致癌活性的修饰蛋白。我们在小鼠模型 C/EBPα-S193A 中研究了肝癌，在一大群人 HBL 样本和 Pten/p53 双敲除小鼠中，发现这些癌症的特征是 C/EBPα 升高，其在 Ser190/193 处去磷酸化。我们发现去磷酸化的 C/EBPα 与癌症干细胞一起产生癌前病灶，从而导致 HCC 和侵袭性 HBL。C/EBPα 依赖性肝细胞去分化为癌症干细胞，包括肝细胞增殖增加，随后产生多核肝细胞，随后出现具有 delta 样 1 同源阳性核内包涵体的肝细胞。我们进一步分离了 C/EBPα 依赖性多核肝细胞，发现它们具有肿瘤起始细胞的特征，包括干细胞标志物的升高。在侵袭性 HBL 患者和具有肝癌易感性的患者中观察到 C/EBPα 依赖性癌症干细胞。结论：成人 HCC 和侵袭性小儿肝癌的最早阶段具有相同的特征，包括肿瘤抑制因子 C/EBPα 转化为致癌亚型，这进一步产生癌前病灶，肝细胞去分化为癌细胞，导致肝癌。（肝病学 2018 年；67：1857-1871）。