I’m very grateful to World Cancer Research Fund for this grant, as it covers new and largely unexplored angles in liver diseases. In the Translational Control of Cell Cycle and Differentiation lab at IRB Barcelona, we focus our research in the gene expression regulation mediated by the CPEB proteins, which play key roles in a variety of diseases, including autism, breast cancer and fatty liver. Our findings indicate that these proteins are responsible for the metabolic reprogramming that takes place in obesity and that could promote cell malignancy.
– Prof Raul Mendez
- Grant awarded: November 2020
Background
Liver cancer is among the deadliest cancers worldwide and its prevalence is dramatically increasing due to the global epidemic of obesity and overweight. A liver transplant currently represents the only chance of long-term survival for patients with liver cancer. However, this procedure is highly expensive and many patients die on the waiting list due to donor organ shortage.
In addition, many patients are also considered ineligible for a liver transplant because of other conditions they have, such as obesity. New treatment options are therefore urgently required to reduce the burden of liver cancer worldwide. So it is essential to better understand the molecular and cellular causes linking obesity and liver cancer.
Aims and objectives
Although most liver cancers develop from chronic liver damage, studies mainly focus on the endpoint and rarely look at the evolution from early stages of the disease. In this project, we explored the progression of the disease, from chronic liver damage caused by diet to the development of cancer. To do this, we explored a possible new “Achilles heel” of cancer.
A tumour in obesity-driven liver cancer can overrule the genes that are involved in normal liver functions, causing them to instead promote its own growth. If we can understand this, we can use it against the cancer, opening a new window of opportunity to treat liver cancer and set the basis for new drug development strategies.
Methods
Currently, most of our knowledge about liver cancer comes from transcription – this is the process by which DNA is read and copied so that each cell in the body knows what its function is and what to do. Instead we looked at what happens in the cell post-transcription.
This advances our understanding of not only liver cancer tumours but also of the dynamic interplay between the tumour and its cellular surroundings in the body. It helps us understand what happens in the body and cells before the tumour is formed, such as how fatty liver disease progresses to liver cancer. Importantly, we used data from men and women.
Results
We identified a protein called CPEB4, as a key player in the development of liver cancer. CPEB4 helps control the activity of certain genes, including one that affects how cancer cells respond to ferroptosis, a type of cell death. In addition to its role in cancer, CPEB4 was also identidied as a driver and theraputic target to combat obesity.
When we blocked CPEB4 production in mice, this protected against weight gain. The absence of CPEB4 also reduces the negative impact of a high-fat diet on gut health, helping to shift the microbiome towards a more favorable and balanced composition.
Conclusion
This study identifies CPEB4 as a driver and therapeutic target to combat obesity-driven liver cancer.
Potential impact
By uncovering the role of CPEB4 in liver disease and cancer this research has made significant contibutions to both the scientific and public health landscape; not only advancing the field of liver disease research but opening new doors for understanding the broader implications of RNA-binding proteins in health and disease.
Grant publications
- Pell N, Garcia-Pras E, Gallego J, Naranjo-Suarez S, Balvey A, Suñer C, Fernandez-Alfara M, Chanes V, Carbo J, Ramirez-Pedraza M, Reina O, Thingholm L, Bang C, Rühlemann M, Franke A, Schierwagen R, Rheinwalt KP, Trebicka J, Mendez R, Fernandez M. Targeting the cytoplasmic polyadenylation element-binding protein CPEB4 protects against diet-induced obesity and microbiome dysbiosis. Mol Metab. 2021 Dec;54:101388. Epub 2021 Nov 10. PMID: 34774811; PMCID: PMC8711066.
- M. Eugenia Delgado, Salvador Naranjo-Suarez, Marta Ramírez-Pedraza, Beatriz I. Cárdenas, Carmen Gallardo-Martínez, Alexandra Balvey, Eulalia Belloc, Judit Martín, Mark Boyle, Raúl Méndez, Mercedes Fernandez. CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis. JHEP Reports, Volume 7, Issue 3, 2025, 101296, ISSN 2589-5559.
