Scientists link proteins that keep cells multiplying to cancer

In In The News by Barbara Jacoby



Cancer is a disease where cells become abnormal and multiply out of control. Until now it was thought the proliferation of cancer cells was controlled by transcription factor proteins. But now a new study suggests another family of proteins may also be involved.

The study – led by the Massachusetts Institute of Technology (MIT) – finds that a family of RNA-binding proteins known as Musashi proteins are involved in the control of cancer, particularly in a subtype of breast cancer.

The researchers suggest the Musashi proteins may force cancer cells to change to and remain locked in a state where they multiply at a faster rate.

Cells in states of increased proliferation are often seen in cancer and embryonic development. Until this study, biologists thought cells were put in this state by transcription factors – proteins that switch genes on and off by acting on DNA to control the rate at which DNA-encoded instructions are transcribed to messenger RNA to relay to cell processes.

Musashi proteins seem able to lock cells into state of faster proliferation

But the new study shows that Musashi proteins – a family of RNA-binding proteins that influence gene expression by acting on RNA messenger molecules – also seem to be able to lock cells into a state of faster proliferation.

There are about 500 different RNA-binding proteins in human beings.

Co-lead author Dr. Yarden Katz, of MIT’s Department of Brain and Cognitive Sciences, says scientists are beginning to find there is a lot of RNA processing going on in mammal cells:

“RNA is processed at several points within the cell, and this gives opportunities for RNA-binding proteins to regulate RNA at each point. We’re very interested in trying to understand this unexplored class of RNA-binding proteins and how they regulate cell-state transitions.”

The new study sheds light on a group of RNA-binding proteins that is not well-known. Musashi proteins are abundant in neural stem cells and they have also been found in tumors, including glioblastoma, a very aggressive form of brain cancer.

Dr. Katz explains that Musashi proteins are normally involved in “marking stem and progenitor cells, but they get turned on in cancers. That was intriguing to us because it suggested they might impose a more undifferentiated state on cancer cells.”

Musashi proteins appear to regulate epithelial-to-mesenchymal transition (EMT)

For their study, the team observed what happened to genes when they changed levels of Musashi proteins in neural stem cells.

They found changes to Musashi protein levels altered genes associated with a process through which cells transform from a state where they stick to each other to a state where they become loose and travel easily. The process is called epithelial-to-mesenchymal transition (EMT).

EMT is known to occur in breast cancer. When the researchers turned their attention away from brain tissue and started examining breast tissue, they found Musashi proteins were highly expressed in a type of breast tumor known as luminal B tumors.

Luminal B tumors are not metastatic – that is they do not normally spread to other parts of the body – but they are aggressive and grow fast.

To confirm that it was the higher expression of Musashi proteins that was causing the tumors to grow faster, the team ran another experiment where they switched off or “knocked down” the Musashi proteins – thus disabling their influence on messenger RNA – in breast cancer cells grown in the lab.

The researchers found that knocking down the Musashi proteins in the breast cancer cells forced the cells out of the epithelial state. And if they boosted Musashi protein expression in mesenchymal cells – they transitioned to the epithelial state, the state associated with higher rates of proliferation.

EMT known to be important in cancers like breast cancer

Dr. Katz explains that the Musashi proteins appear to be regulating the EMT state changes in the cells, which other studies show are important in cancers like breast cancer.

Mushashi proteins are normally turned off after embryonic development, when EMT is a necessary process for regulating all the growth and differentiation that goes on. The team is now trying to work out how the proteins get turned back on again in cancer cells.

Dr. Katz says it is too early to say whether Musashi proteins would make good targets for cancer drugs – but they may be useful as markers to help diagnose what state cancer cells are in:

“It’s more about understanding the cell states of cancer at this stage, and diagnosing them, rather than treating them,” he explains.

The National Institutes of Health funded the study.