What do solid tumours, certain congenital types of deafness and rheumatoid arthritis have in common? A deregulation in the function of the protein KIAA1199! In a study published in Nature communications, researchers from the University of Liège reveal the link between this protein and a receptor known as EGFR, a key protagonist in tumour development and progression. A link that could be of importance for these human diseases...

Familial cylindromatosis, also known as turban tumour syndrome, is a genetic disease that leads to the formation of large benign tumours, essentially on the head. They result from the hyperproliferation and the prolonged survival of keratinocytes, the predominant cell type in the epidermis. "One of the reasons why these people spontaneously develop these tumours is that they exhibit an overexpression of the protein Bcl-3 in their keratinocytes", explains Professor Alain Chariot, project leader at GIGA’s Laboratory of Medical Chemistry at the University of Liège.
 While studying this disease, Alain Chariot and his colleagues could not imagine where their research was going to bring them... They focus their work on the identification and characterization of proteins that promote tumor development and progression up to metastasis. “We dissect at the molecular level all protagonists that somehow play some role in the development and progression of cancer”, Alain Chariot specifies. “Once we have a precise idea on how these proteins intervene, we inactivate the corresponding genes in mice in order to address the consequences on tumor development”. For this purpose, the scientists combine a whole series of approaches: microarray (DNA chip), transgenesis, and molecular and cellular biology. In some cases, the inactivation of a gene manages to block or to delay tumour development and the researchers can subsequently record the protein in question as one main protagonist in tumour development.

A protein that activates some key survival pathways

Within the framework of its research on familial cylindromatosis, Alain Chariot’s team studied the cellular consequences of overexpressing Bcl-3. What happens in cells when this protein is expressed in large amounts? "We used the DNA chip approach to identify all gene candidates induced following the overexpression of Bcl-3 in immortalized keratinocytes. The most intensively induced candidate upon Bcl-3 overexpression was KIAA1199". Following these observations, the researchers made the link with another disease in which keratinocytes are proliferating too much:  cervical cancer. “This cancer results from an infection by the oncogenic human papillomavirus (HPV). When patients develop this type of cancer following HPV infection, they also exhibit large amounts of the Bcl-3 protein, which leads to the overexpression of its target gene KIAA1199", explains Alain Chariot, who established a fruitful collaboration with the team of Professor Philippe Delvenne at GIGA’s Laboratory of Experimental Pathology, ULg. But why does HPV induce this gene? It was still unclear at that time what the KIAA1199 protein was actually doing. The researchers from Liège provided some answers to this question in an article published in Nature Communications (1). “We show that this protein promotes cell survival in keratinocytes. If we deprive these cells from the protein KIAA1199, the keratinocytes die. The overexpression of this gene is therefore one of the reasons why patients develop cervical cancer, because HPV triggers the expression of this protein to sustain cell survival in the infected keratinocytes. As they survive longer, cancerous cells can accumulate and tumor growth occurs", Alain Chariot reveals.

(1) Kateryna Shostak, Xin Zhang, Pascale Hubert, Serkan Ismail Göktuna, Zheshen Jiang, Iva Klevernic, Julien Hildebrand, Patrick Roncarati, Benoit Hennuy, Aurélie Ladang, Joan Somja, André Gothot, Pierre Close, Philippe Delvenne & Alain Chariot. NF-κB-induced KIAA1199 promotes survival through EGFR signalling. Nature communications| 5:5232 | DOI: 10.1038/ncomms6232 |