Molecular signalling pathway of liver cancer development decoded

What is it about?

Hepatocellular carcinoma (HCC), a malignant disease of liver cells, is a leading cause of cancer-related deaths. This is due to its increasing incidence, linked to the obesity pandemic, and the lack of effective treatments for advanced forms. In this study, we built on previous findings that indicated the involvement of transcription factors (TF) from the AP-1 family—comprising pairs (dimers) of Jun and Fos proteins—in HCC development. TFs are protein complexes that control gene expression and commonly implicated in diseases. To study HCC pathogenesis and explore potential therapies, we leveraged genetic engineering to generate novel experimental mouse models expressing specific AP-1 dimers in liver cells in a switchable manner. Experiments conducted with these mice unveiled that the AP-1 TF formed by c-Jun and Fra-2 triggered spontaneous HCC in adult mice. Remarkably, we observed regression of the majority of tumors by switching off c-Jun and Fra-2 expression, while those that evaded regression maintained elevated levels of another TF: c-Myc. Furthermore, we also demonstrated that tumor growth can be halted by treating the mice with a drug blocking c-Myc, indicating that the molecular signalling pathway we uncovered is a promising foundation for further HCC research and the development of new therapeutic approaches.

Featured Image

Photo by Ricky Kharawala on Unsplash

Photo by Ricky Kharawala on Unsplash

Why is it important?

Despite a wealth of studies, there is no effective therapy for HCC due to limited mechanistic knowledge and the lack of biomarkers to select patients that could benefit from a specific (targeted) therapy. HCC prevention by limiting viral (B and C) hepatitis, currently accounting for 75% of liver cancer deaths, remains therefore the key strategy. Immunotherapies, now part of the first-line treatment for advanced HCC, are costly and have yet to fulfill their promises while Sorafenib is still the HCC standard of care in low income countries, despite limited efficacy. This study establishes a mouse model for HCC research that could be used to increase our understanding of HCC pathogenesis, identify biomarkers and allow preclinical testing of HCC drugs. In the future, our work might help achieve widespread access to affordable and more efficient HCC treatment.

Perspectives