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Function of protein involved in liver cancer discovered

The involvement of clathrin in the development of liver cancer has been described for the first time, which could lead to more targeted therapy.

Researchers have described for the first time the involvement of a cell membrane protein, called clathrin, in the development and progression of liver cancer.

According to the team, clathrin expression in advanced liver cancer encourages more tumour growth, so could therefore be a viable target for the condition. 

Clathrin is key in the process of internalisation of molecules from the extracellular space into the cell, called endocytosis. In this process, the cell membrane folds, creating vesicles with a cladded structure.

The research team from Bellvitge Biomedical Research Institute (IDIBELL), Spain, led by Dr Isabel Fabregat, has shown that liver cells with invasive features have high levels of clathrin. Specifically, they showed that high expression levels of clathrin correlate with the activation of the pro-tumourigenic pathway of a known hepatic carcinogenesis actor: TGF-β. 

TGF-β has a dual role: in normal conditions or in early stages of carcinogenesis, it plays a tumour-suppressive role. But in advanced stages of liver cancer, tumour cells have acquired capabilities to escape its suppressor functions and respond to TGF- β by inducing cell migration and invasion, thus contributing to tumour spreading.

For this change in cellular behaviour to take place, TGF-β activates the EGF receptor pathway (EGFR) in tumour cells. The new results have shown that clathrin is essential in the endocytosis of EGFR, a decisive step for the activation of this pathway by TGF-β.

In vitro experiments of this work have allowed the researchers to demonstrate that clathrin cell levels determine, via EGFR, the function of TGF-β. If the expression of clathrin is eliminated, the cells die.

There is a positive correlation between the expression of TGF-β and clathrin in samples of hepatocellular carcinoma patients”

On the contrary, high levels of clathrin promote the pro-invasive and tumourigenic character of the cells. The reason for this effect must be found in the functionality of the EGFR pathway: the elimination of clathrin results in an inhibition of this signalling pathway. Researchers have shown that TGF-β is capable of inducing clathrin synthesis, ultimately encouraging a self-stimulation loop.

The study has also demonstrated that clathrin expression increases during hepatic tumourigenesis both in humans and mice and its expression changes the response to TGF-β in favour of anti-apoptotic/pro-tumorigenic signals. There is a positive correlation between the expression of TGF-β and clathrin in samples of hepatocellular carcinoma patients. Patients expressing high levels of TGF-β and clathrin showed a worse prognosis and reduced survival.

The research was described in an article published in the Journal of Hepatology.

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