Mutation in a tumor suppressor gene found to fuel liver cancer’s growth
A UCLA research team from the David Geffen School of Medicine and the Jonsson Comprehensive Cancer Center has discovered that a gene called Axin1 can help hepatocellular carcinoma liver cancer proliferate when it has a mutation. Axin1 normally plays a role in suppressing tumors from developing. But when a loss-of-function mutation is present, the gene can assist tumors in gaining access to large amounts of nutrition and fuel their growth.
Hepatocellular carcinoma is the most common form of liver cancer. It often occurs in people who have a chronic liver disease such as hepatitis B and C.
Since cancer cells must compete with normal cells for their nutrition, a UCLA research team led a study on how these liver cancer cells gain access to nutrients. The study revealed that mutations in the tumor suppressor gene, Axin1, play a key role in driving the nutrition that fuels the growth of hepatocellular carcinoma. This occurs through a process called macropinocytosis, where cancer cells ingest liquid with dissolved molecules as a primary source of energy.
During normal cellular activity, the Axin1 gene, together with Adenomatous Polyposis Coli, the major tumor suppressor in colorectal cancer, repress a molecular signaling pathway called Wnt. Axin1 and Adenomatous Polyposis Coli facilitate the activity of an enzyme called Glycogen Signaling Kinase 3 (GSK3). This process adds phosphates to many proteins.
But when there is mutation of Axin1, loss of Adenomatous Polyposis Coli, or pharmacological inhibition of GSK3, this mutation triggers massive amounts of macropinocytosis, which allows cancer cells to ingest large amounts of energy.
The researchers also discovered that when introducing a normal Axin1 gene that does not have a mutation to the mutant cell line, regular cellular activity is restored.
For the study, UCLA researchers focused on cancer cell metabolism by investigating the molecular switches that activate macropinocytosis in liver cancer cells that have a mutant Axin1 and Adenomatous Polyposis Coli genes.
Macropinocytosis is emerging as a critical process in the study of cancer because it enables tumors to devour large amounts of fluid to generate nutrients for growth. Sustained macropinocytosis has been observed in many cancers such as pancreatic ductal carcinoma, bladder cancer, prostate cancer, lung cancer, and now in hepatocellular carcinoma.
Understanding cancer cell metabolism can help researchers find ways to suppress their growth.
The UCLA team that contributed to this study include Lauren Albrecht, Nydia Tejeda- Muñoz, Maggie Bui, Andrew Cicchetto, Daniele Di Biagio, Gabriele Colozza, Ernst Schmid, Stefano Piccolo, Heather Christofk, and Dr. Edward De Robertis.
The UCLA researchers have affiliations with the Department of Biological Chemistry at the David Geffen School of Medicine at UCLA, the UCLA Jonsson Comprehensive Cancer Center, and the University of Padua School of Medicine.
The research is published online in Cell Press.
Funding for the study was provided by the National Institutes of Health and the Howard Hughes Medical Institute.