Study Links p62 Protein to Likelihood of Liver Cancer Recurrence

Cancer researchers have linked levels of the ubiquitin-binding autophagy receptor protein p62 (Sequestosome-1) in liver cells to the development and recurrence of hepatocellular carcinomas (HCCs).

The p62 protein is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in pre-malignant liver diseases and most types of HCCs. To examine the relationship between p62 and HCCs, investigators at the University of California San Diego (USA) and the Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA, USA) analyzed non-cancerous liver samples collected from individuals who had undergone previous treatment to completely destroy their liver cancers.

The investigators reported in the May 19, 2016, online edition of the journal Cancer Cell that 79 of 121 specimens contained detectable levels of p62. Individuals with high levels of p62 were significantly more prone to cancer recurrence and less likely to survive cancer-free than those with low levels or no p62. The same correlation was found for an additional 450 liver cancer patients whose genomic data and clinical records were available in national research databases.

In a mouse liver cancer model it was found that high levels of p62, which alone were sufficient to trigger tumor formation, activated the proteins NRF2 (Nuclear factor (erythroid-derived 2)-like 2) and mTORC1 (mammalian target of rapamycin (mTOR) complex 1), inducted c-Myc (v-myc myelocytomatosis viral oncogene homolog protein), and protected HCC-initiating cells from oxidative stress-induced death. Extended cell survival allowed accumulation of oncogenic mutations that triggered tumor formation. HCCs did not form spontaneously in the absence of p62.

“By defining factors that allow liver cells to progress from pre-cancer to cancer, we were able to find one - p62 - that we can also use to predict a liver cancer patient’s outcome following full removal of a previous liver tumor,” said senior author Dr. Michael Karin, professor of pharmacology and pathology at the University of California, San Diego.

“Our new study illustrates that p62 is necessary and sufficient to induce liver cancer in mice, and that its high expression level in liver tissue surrounding a tumor predicts recurrence of the disease after tumors are removed,” said contributing author Dr. Jorge Moscat, deputy director of the cancer center at the Sanford Burnham Prebys Medical Discovery Institute. “We believe that small molecules that interfere with p62 may be useful for preventing the progression of chronic liver disease to liver cancer.”

Related Links:
University of California San Diego
Sanford Burnham Prebys Medical Discovery Institute