New insight into the role of autophagy in tumorigenesis.

Abstract

Autophagy plays an important role in maintaining cellular homeostasis. Its dysfunction can cause many diseases, including neurodegenerative diseases, metabolic diseases and cancer. The role of autophagy in carcinogenesis is complex, as it was shown to have pro-tumorigenic functions in some reports, but anti-tumorigenic functions in others. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we had previously demonstrated that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after they were treated with the carcinogen diethylnitrosamine (DEN), which induced HCC in wild-type mice. Our recent studies indicated that the inability of mice to develop HCC when autophagy was impaired was at least partially due to the activation of the tumor suppressor TP53, which suppressed the expression of NANOG, a transcription factor critical for the self-renewal and the maintenance of cancer stem cells (CSCs).