Uncontrolled 'cAMP' Molecule Linked to Rare Liver Cancer Development: Study
Sun, April 18, 2021

Uncontrolled 'cAMP' Molecule Linked to Rare Liver Cancer Development: Study


A new study discovered a protein associated with a rare type of liver cancer. If the protein goes out of control, it can enable processes of abnormal cellular growth.

The discovery of the mystery protein linked to fibrolamellar carcinoma was led by the University of California – San Diego (UCSD), a US public research university. Researchers found that the molecule cyclic AMP or cAMP could travel freely inside cells. Its involvement in numerous processes was identified by engineered fluorescent probes. Uncontrolled cAMP within cells could activate signals for unregulated cell growth, which would result in malignancy. They published their findings in the journal Cell.

Liver Cancer and Liver Cirrhosis Rates in the US

Liver cancer is characterized by abnormal appearance and behavior of normal cells in the liver. The abnormalities are related to the uncontrolled growth of cells, which do not function like healthy liver cells. According to the National Cancer Institute of the National Institutes of Health, hepatocellular carcinoma (HCC) is the most common type of liver cancer. The usual risk factors of HCC are chronic liver infection, such as hepatitis B and C, and liver cirrhosis.



Based on Statista, a German portal for statistics, adults aged 75 to 84 years had the highest prevalence rate of liver cirrhosis at 35.5 per 100,000 population in 2017 in the US. It was followed by adults aged 65 to 74 years at 35.1, adults aged 55 to 64 years at 34.2, adults aged 85 years and older at 29.3, adults aged 45 to 54 years at 20.2, adults aged 35 to 44 years at 7.6, and adults aged 25 to 34 years at 2.1 per 100,000 population.

Meanwhile, adults aged 65 to 69 years had the highest prevalence rate of liver cancer at 39.5 per 100,000 population in 2017 in the US. It was followed by adults aged 75 to 79 years at 39.4, adults aged 80 to 84 years at 38.4, adults aged 70 to 74 years at 35.7, adults 60 to 64 years at 33.9, adults 85 years and older at 31.2, adults aged 55 to 59 years at 21.4, adults aged 50 to 54 years at 9.5, adults aged 45 to 49 years at 3.8, adults aged 40 to 44 years at 1.8, children aged less than one year at 1.3, adults 35 to 39 years at 0.9, children aged one to four years at 0.6, adults aged 30 to 34 years at 0.5, adults aged 25 to 29 at 0.3, people aged 15 to 24 years at 0.2, and children aged five to 14 years at 0.1 per 100,000 population.



Molecule Linked to Rare Liver Cancer

One of the rare types of liver cancer is called fibrolamellar carcinoma or FLC. It is more common among teens and adults younger than 40 years. Unlike other liver cancer types, FLC can occur in people with healthy livers. The malignancy can develop even if their livers have not been damaged by alcohol consumption or viral infections. Scientists believe that FLC is caused by a chromosome that has been broken and put back together incorrectly. This results in cells to malfunction and become cancerous. But the mechanism behind it is still a mystery.

At UCSD, researchers might have an answer to the mystery of FLC development. Their latest research uncovered a molecule that could trigger the processes behind FLC. The molecule – cAMP protein – could be found within cells due to its extensive involvement in various cellular processes. However, its ability to induce malignancy was not fully determined before. Their study showed that cAMP spillover might be a factor.

"In this study, we showed that this cancer-causing fusion protein disrupts cAMP-containing membraneless organelles, allowing cAMP to flood the cell," said Jin Zhang, the corresponding author of the study and professor of pharmacology at UCSD.



Researchers explained that cAMP might travel freely inside cells to handle numerous processes. It could even appear in the right place and the right time to respond to environmental changes. Based on that, the molecule would be critical in different cellular functionalities. Aside from cAMP, calcium would be involved in signaling human cells to accomplish tasks. The actions of these two could be found in binding proteins, kinases, and scaffold proteins.

To track and observe cAMP, the team engineered fluorescent probes by combining the CRISPR gene-editing tool and biosensor technologies. The probes allowed them to see the molecule in a completely different way. The probes showed the noncanonical capture of cAMP. Cellular functions were thought to occur in membrane-enclosed organelles, like mitochondria. But the major protein binding cAMP could form in membraneless or no-wall organelles.

The molecule would be sequestered by membraneless organelles. Due to the lack of walls, cAMP could spill and affect other functions when the organelles were destroyed. The improper spillover of cAMP would trigger uncontrolled cell growth. This was connected to FLC wherein most patients could exhibit a mutation in cAMP-regulated protein. That protein would be often joined by an unrelated protein, yielding a hybrid protein. The hybrid protein indicated incorrect merging and could drive FLC tumors. Though, how the hybrid protein specifically results in cancer is yet to be discovered.

In real-life interpretation, the hybrid protein could disrupt membraneless organelles filled with cAMP. Once destroyed, a cell would be filled with the molecule. Liver cells that lost the ability to form membraneless organelles would eventually undergo uncontrolled cell growth. Thus, unmanaged quantities of cAMP within cells outside of organelles could lead to malignancy.

Furthermore, the membraneless organelles were estimated to occupy less than 1% of a cell's volume. But their capacity could hold up to 99% of the cell's cAMP. If the organelles were disrupted by other proteins, the molecule would spill and alter the processes of the cell. And since cAMP could be found in every human cell, the same incident in the liver might be happening in brain cells and heart cells, among others.

The team is now investigating how the molecule and membraneless organelles function in other specialized cell types. If they can find ways how to prevent the cAMP spillover, it may lead to potential therapies.