Scientists have discovered that a small group of immune-regulating molecules could trigger lymphoma, according to a study published in the The Embo Journal.

Researchers from The Scripps Research Institute (TSRI) in California have found that six microRNA molecules – short molecules found in nearly all animal and plant cells, may be responsible for lymphoma when overproduced.

Each microRNA acts as a “dimmer switch” for one or more genes, according to the researchers. They work by binding to the genes and preventing them from being translated into proteins. They are then able to regulate various cell processes.

The six microRNAs, called miR-17~92, are encoded by a single gene on chromosome 13. The researchers say that previous studies show that immune-related and developmental processes are controlled by miR-17~92, dependent upon the type of cell it is expressed in.

Previous research has already demonstrated that microRNAs can be overproduced in different lymphomas, but this most recent research shows that overproduced clusters of microRNAs can be a main cause of the cancers.

For the study, the researchers analyzed a colony of genetically engineered mice, created senior investigator of the study, Professor Changchun Xiao.

Prof. Xiao explains that the mice contained an artificial gene segment that could be activated to overproduce MiR-17~92 in any chosen cell type.

Overproduction occurred in anti-body producing immune cells in the mice, called B cells. These are the cells that Burkitt lymphoma originates from – a fast growing form of non-Hodgkins lymphoma.

Results of the study showed that 80% of the mice developed various types of lymphomas within one year of overproduction of miR-17~92.

Prof. Xiao explains:

“It was striking that this very high rate of lymphoma came from only a three-to-fivefold over-expression of miR-17~92 in B cells, whereas human Burkitt lymphomas typically show more than tenfold over-expression.”

From understanding that miR-17~19 can trigger B cell lymphomas, the researchers then looked at how microRNA clusters work in mouse models whose B cells are engineered to over-express a cancer-inducing “oncogene” called myc.

This is a gene whose hyperactivity is a characteristic of Burkitt lymphoma cases in humans, and triggers the overproduction of miR-17~92.

Results showed that the overproduction of miR-17~92 in the mice appeared to significantly trigger the development of lymphoma.

Maoyi Lai, co-lead author of the study, explains:

Deleting miR-17~92 from the B cells of these mice significantly delayed the development of lymphomas and extended the mice’s survival.

Looking more closely, we found that the lymphomas that did develop in these mice originated only from B cells in which miR-17~92 had managed to escape deletion and was still being overproduced.”

Further research was carried out to determine how miR-17~92 triggers cancer so powerfully. This was done by using a technique that locates the binding sites of microRNAs on messenger RNAs.

The researchers found a large proportion of the binding sites were genes that usually stop cancer cell growth and survival, meaning miR-17~92 is instead promoting this.

Prof. Xiao explains:

“It affects so many important pathways that even a modest miR-17~92 over-expression apparently moves the cell from a normal growth and survival mode into the cancerous state.”

The research team injected chemical inhibitors into the mice with miR-17~92 driven lymphomas, and found the tumors shrank and mouse survival was prolonged.

They conclude they are now analyzing how creating inhibitors that target both growth and survival could be implemented to target miR-17~92 microRNAs directly.