Protein lost in lung cancer reveals hidden layer of gene control

Scientists at Barts Cancer Institute, Queen Mary University of London, have uncovered an important way that cells keep their genes under control. The discovery could help explain one of the earliest molecular changes that occurs during the development of lung cancer.

The study, published in Science Advances, reveals that a protein called LIMD1, which is frequently lost in lung cancer, plays a much bigger role in controlling gene activity than scientists previously realised. The findings uncover a previously hidden layer of gene regulation and may provide new insight into how normal cells begin to lose control during the earliest stages of cancer.

The research was led by first author Dr Alex Crozier, co-corresponding author Dr Kunal Shah and senior author Professor Tyson V. Sharp at Barts Cancer Institute.

Lung cancer remains the UK’s leading cause of cancer death, and long-term survival is still much lower than for many other common cancers (Source: Cancer Research UK). Improving these outcomes will require a deeper understanding of the early molecular changes that allow the disease to develop.

Tiny molecules that can shape a cell’s fate

Although every cell in your body contains essentially the same DNA, brain cells, lung cells and skin cells all behave very differently. This is because each cell uses a different selection of its genetic instructions.

Many genes in our DNA contain instructions for making proteins, molecules that carry out a vast array of functions in our cells. To use these instructions, a cell first produces a working copy of the instructions called messenger RNA, a chemical cousin of DNA that carries the message to the cell’s protein-building machinery.

MicroRNAs provide one way for cells to adjust protein production quickly and precisely. These tiny RNA molecules do not contain instructions for making proteins themselves. Instead, they act like biological dimmer switches, turning down the production of proteins from selected genes. To do this, microRNAs work together with a protein called AGO2, which helps them find the correct RNA messages inside the cell.

A single microRNA can help control hundreds of genes, allowing cells to grow, adapt and stay healthy. When disrupted, the effects can impact networks of genes relevant to many diseases, including cancer.

Since their discovery more than 30 years ago, microRNAs have become the focus of a major field of research into how cells control their genes. Their fundamental importance was recognised in 2024, when the Nobel Prize in Physiology or Medicine was awarded for their original discovery. Yet many of the rules governing how microRNAs control their targets remain a mystery.

Extending the rules of microRNA control

In the new study, the team focused on LIMD1, a protein that has several roles in the healthy functioning of cells and can also help suppress tumour formation.

LIMD1 acts like a molecular bridge. One part binds to AGO2, the core protein that carries the microRNA, while another connects AGO2 to the wider machinery needed to silence its target message effectively. When the cell loses that molecular bridge, AGO2 becomes less able to engage many of its targets effectively and silence them.
The team used gene editing to reduce or remove LIMD1 from non-cancerous human lung cells grown in the laboratory. They then used an advanced technique to capture AGO2 together with the microRNAs and messenger RNAs bound to it, allowing them to examine targeting across the cell.

Without LIMD1, successful interactions between microRNAs and their targets fell by around 60%. As a result, many proteins that would normally be kept under tight control became more abundant.

“For years, researchers have mainly tried to predict which genes microRNAs will regulate by looking at RNA sequences,” says Dr Alex Crozier. “But these sequence-based rules explain only around half of the variation in how strongly microRNAs repress their targets. Our study shows that proteins like LIMD1 can also help determine whether AGO2 successfully engages and silences a target, revealing an additional layer of microRNA control.”

What do these results mean for lung cancer?

The team identified a group of five genes that were particularly strongly affected when LIMD1 was lost and examined the same group of genes in public datasets from people with lung cancer.

Tumours generally had less LIMD1 and higher levels of this five-gene signature than nearby healthy tissue. Patients with this pattern tended to have poorer outcomes,

While further research is needed, the findings provide an important starting point for understanding how the earliest changes in lung cancer alter the way genes are controlled.

Looking ahead

The discovery could have implications beyond lung cancer. Researchers around the world are developing RNA-based medicines that use small RNAs to turn down disease-causing genes. Understanding why some RNA targets are controlled successfully while others are not could help make these treatments more precise and effective.

“We believe we’ve uncovered an important missing piece of how cells control gene expression,” says Professor Sharp. “LIMD1 is likely to be just one example of a larger family of proteins that guide this process. As we discover more of them, we expect to uncover entirely new principles of gene regulation that could ultimately help identify better biomarkers and future treatment opportunities.”

The study benefited from specialist RNA facilities at BCI, as well as additional expertise and feedback from other members of our RNA hub. It was supported by BCI core facilities, including the and Microscopy facilities, and involved collaborators from Eclipse BioInnovations and the universities of York, Oxford, Manchester and Essex.

This research was funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Barts Charity and Cancer Research UK. Dr Alex Crozier was supported by the London Interdisciplinary Doctoral Training Programme. For full funding details, please see the original paper.