Potential role of p62 in tumor development.

p62 is a ubiquitously expressed cellular protein conserved in metazoa but not in plants and fungi, and is known as one of the selective substrates for autophagy. This protein is localized at the autophagosome formation site and directly interacts with LC3, an autophagosome-localizing protein, and it is incorporated subsequently into the autophagosome and finally degraded. Impaired autophagy is accompanied by the accumulation of p62, followed by the formation of aggregates positive for p62 and ubiquitinated proteins because of the nature of both self-oligomerization and the ubiquitin-binding capacity of p62. The p62-positive aggregates observed in hepatocytes of liver-specific Atg7-deficient mice are completely dispersed by additional loss of p62, suggesting the involvement of p62 in the formation of disease-related inclusion bodies. Importantly, similar aggregates known as Mallory bodies and intracellular hyaline bodies have been identified in hepatocellular carcinoma (HCC). However, the pathophysiological significance of such aggregates remains unclear. Recently, we identified the role of p62-positive aggregates in human HCC and autophagy-deficient tumors in tumor development through persistent activation of Nrf2, a transcription factor responsible for stress response.