What allows the NOX4 protein to act as a molecular brake on liver cancer

Liver cancer is the sixth most common in the world and the third with the worst prognosis. According to the World Health Organization (WHO), in 2020 a total of 830,000 deaths were attributed to it; a figure in constant growth that is only surpassed by those that are recognized for lung cancer and colon cancer. There are several risk factors for this type of tumor, such as excessive alcohol consumption, obesity, sedentary lifestyle, viral infections caused by hepatitis B and C, and drug use, among others. It should be noted that, in terms of incidence and mortality, the figures are higher in men than in women. Although great progress has been made in recent years, progress is still needed in understanding the molecular mechanisms of this disease and in the design of new therapeutic options.

Now, a study published in the academic journal Hepatology highlights the importance of a protein called NOX4 in the development of hepatocellular carcinoma, which is the most aggressive and unfortunately the most common form of liver cancer. Using genetically modified mice, cell cultures and human tumor samples, the team led by Isabel Fabregat, head of the TGF-beta and Cancer group at the Bellvitge Biomedical Research Institute (IDIBELL), located in Hospitalet de Llobregat and part of the CERCA institution of the Generalitat of Catalonia, has managed to identify the molecular mechanisms regulated by this protein and has deciphered its protective role against cancer.

“Although liver cancer cells are especially avid for glucose and lipids, which allows them to multiply rapidly, NOX4 slows down these processes,” explains Fabregat, who is also a professor at the University of Barcelona (UB) and group leader of the Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBEREHD) in Spain. She adds: “When NOX4 activity is low, cellular metabolism is reprogrammed and oxidative stress is caused, which favors the tumor to proliferate more and increase its ability to invade other tissues. Consequently, the levels of NOX4 can determine the evolution of liver cancer”.

Members of the research team. (Photo: IDIBELL)

During the onset of liver cancer, an oxidative microenvironment is created that causes cellular stress, which activates NOX proteins. However, not all proteins in the family have the same functions. While NOX4 has a protective effect, as this study has revealed, NOX1 contributes to cancer progression. “The results indicate that NOX1 favors an increase in oxidative stress, a process that NOX4 manages to reduce”, explains Irene Peñuelas, postdoctoral researcher at IDIBELL, as well as at CIBEREHD and first signatory of the study.

The NOX proteins would be achieving these changes through the regulation of the transcription factors MYC and NRF2, responsible for the expression of many genes involved in cancer. “We have seen that in the absence of NOX4, the expression of NOX1 or NOX2 is increased, which causes an increase in the activity of NRF2 and MYC, which are responsible for changes in the mitochondria and a reprogramming of the oxidative metabolism, increasing the energy capacity of the cell”, indicates Peñuelas.

In fact, previous studies by the same group had indicated that the elimination of NOX4 stimulates the proliferation of liver cells. “Therapeutic applications of NOX4 are very broad. We may be interested in inhibiting it to promote liver regeneration in situations of chronic diseases that produce liver fibrosis, or just the opposite, compensating for its lack of activity in cases of cancer to slow down progression”, concludes Fabregat.

The work has been carried out in the context of the CIBER consortium belonging to the Carlos III Health Institute in Spain and has been led by IDIBELL with the participation of professionals from the Catalan Institute of Oncology, the Bellvitge University Hospital and the University of Barcelona in collaboration with national research groups from CIC bioGUNE, the Severo Ochoa Center for Molecular Biology, the Autonomous University of Madrid, IRB Barcelona, ​​and internationally with scientists from University College Dublin in Ireland. (Source: IDIBELL)