Abstract
Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention.
Highlights
Liver cancer is predicted to be the third leading cause of cancer-related deaths by 2030 [1]
To evaluate whether the decreased survival of Alb-Cre+; Atg7fl/fl; Pten+/fl and Alb-Cre+; Atg5fl/fl; Pten+/fl mice was a result of an early tumor onset, we compared the tumorigenesis of Pten+/+ and Pten+/fl mice with an autophagy-deficient background at 140 days
Ptendeficient livers develop steatosis and Hepatocellular carcinoma (HCC) [37], we observed that hepatic Pten deletion alone did not initiate liver damage, inflammation, hepatic stellate cell activation, fibrosis, or a ductular reaction in young livers, but these effects were observed on hepatic deletion of autophagyrelated protein 5 (ATG5) or ATG7
Summary
Liver cancer is predicted to be the third leading cause of cancer-related deaths by 2030 [1]. Hepatocellular carcinoma (HCC) is the major form of liver cancer and develops in patients with chronic liver conditions, including viral hepatitis, as well as alcoholic and nonalcoholic fatty liver disease [2]. Chronic liver injuries lead to inflammation, stromal activation, regeneration, fibrosis, and cirrhosis before progression to HCC [3]. There is clear evidence that autophagy is important in various diseases including neurodegenerative diseases, chronic liver diseases, and cancer [5,6,7]. The role of autophagy in cancer, is complex and not fully understood, with seemingly opposing roles described in different tumors and at different stages of tumor evolution [8,9,10,11,12]. In established tumors, autophagy can adopt a protumorigenic role, for example, by promoting survival under hypoxic conditions [15] and supporting invasion and metastasis [16], and can have a tumor-suppressive role by preventing the proliferative outgrowth of disseminated tumor cells from dormant states at metastatic sites [17,18,19]
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