New Study Sheds Light on New Protein Involvement with Liver Cancer

A team of researchers from the Bellvitge Biomedical Research Institute (IDIBELL) has recently made a novel discovery regarding liver cancer. This work describes the essential role of clathrin, a cell membrane protein, in the development and progression of liver cancer for the first time. The study was recently published in the Journal of Hepatology.

Clathrin is known for its key role in endocytosis, or the internalization of material from outside of the cell. This process involves the folding of the cell membrane to create vesicles with a cladded structure. With these new findings, analyzing clathrin expression in biopsies of liver cancer patients will help physicians better select unique therapeutic approaches for each case.

This research team was led by Isabel Fabregat, PhD, professor at the Faculty of Medicine and Health Sciences of the University of Barcelona and a researcher at the CIBER of Hepatic and Digestive Diseases. Fabregat’s team showed that invasive liver cells express elevated levels of clathrin, which was not previously known to be involved with liver cancer.

They found that this high level of clathrin expression was correlated to the activation of the pro-tumorigenic pathway of a TGF-β, a known hepatic carcinogenesis actor. In doing so, this research offers novel information regarding the complex role of TGF-β in this form of cancer. TGF-β, a cytokine protein, initially functions as a tumor suppressor, promoting cell death and reducing tumor growth. In the advanced stages of liver cancer, however, the tumor cells do not respond to TGF-β’s suppressive actions and respond to the cytokine by increasing cell mobility. This transition leads to metastasis, or the spreading of a tumor.

Previous research from Fabregat and colleagues has found that for this transition in tumor mobility to occur, TGF-β activates the EGF receptor (EGFR) pathway in tumor cells. Existing studies show that EGFR overexpression is found in many cancer samples. These latest findings from Fabregat’s team show that clathrin is essential for the endocytosis of EGFR, which is a key step in the activation of this pathway by TGF-β.

In vitro experiments conducted by IDIBELL researchers have shown that clathrin concentrations determine the function of TGF-β through EGFR. If clathrin expression ceases, the cells can no longer live. If these levels are high, however, they promote the tumorigenic qualities of the cells that lead to metastasis. The researchers surmise that the elimination of clathrin results in the inhibition of the signaling pathway. TGF-β has also been found to be capable of synthesizing clathrin, constituting a positive feedback system.

The study also shows that clathrin expression increases during hepatic tumorigenesis in both humans and mice and that its expression changes the response to TGF-β to favor tumor-developing signals. There is a positive correlation between clathrin and TGF-β expression in samples of hepatocellular carcinoma patients, with high levels of TGF-β and clathrin being associated with a worse prognosis and lower rates of survival.