Researchers unlock mysteries of complex microRNA oncogenes

June 27, 2019

MicroRNAs are tiny molecules of nucleic acid that control gene expression, acting like a dimmer switch to tone down gene output at key positions in the network of information that governs a cell's function. MicroRNAs are important for the day-to-day inner working of cells and especially important during development. They also become profoundly defective in diseases such as cancer. Unlike most other human or animal genes, microRNAs are often encoded in genomes and expressed as beads-on-a-string groupings, known as polycistrons. The purpose for this organisation has, until now, been a mystery.

A new collaborative study, led by researchers at McGill University's Goodman Cancer Research Centre (GCRC), and published in the journal Molecular Cell, set out to solve this mystery, uncovering novel functions for polycistronic microRNAs and showing how cancers such as lymphoma twist these functions to reorganize the information networks that control gene expression.

A discovery thanks to a single oncogene

The researchers made their discovery by examining how strongly the oncogenic microRNA polycistron miR-17-92 was over-expressed in several types of cancer. Surprisingly, this led to only small increases in the mature microRNA expression in the same types of cells. This meant a lot was happening during their biogenesis, especially in cancer, and that there may be more to the purpose of microRNA polycistrons than previously thought.

"Why some microRNAs are expressed as polycistrons, and how cancers such as lymphoma change microRNA biogenesis were not known," explains Dr. Thomas Duchaine, Professor in the Department of Biochemistry at McGill, member of the GCRC and the study's senior author. "We were able to identify some mysterious steps in microRNA biogenesis that occur in cell nuclei, which had been completely missed for the nearly 20 years since the discovery of the conservation of microRNA's."

Understanding microRNA's role in cancer

While researchers knew that microRNAs are important in a broad variety of cancers, how and why was not fully understood. "We discovered an entirely new function for microRNA polycistrons and showed how deep an impact it has in certain types of cancer," notes Dr. Duchaine. The findings will help make sense of many of the genomic reorganizations that occur in microRNA loci in those cancers. "We also think this may be happening in physiological conditions, early in development, in embryonic stem cells for example, in placenta, and in other types of tumours."

Knowing what drives specific types of cancer is critical in stratifying cancer sub-types, in developing new therapeutic strategies, or anticipating treatment outcomes in precision medicine.

"The breadth of the impact of the amplification of a single microRNA locus on the gene networks is pretty amazing, in my opinion," says Dr. Duchaine. "Especially considering that this occurs through a mechanism entirely outside of the traditional targeting function of microRNAs. We are not done understanding microRNA mechanistics. I am always amazed at how complex their functional relationships are within our genomes."

While it is not always easy to anticipate the practical implications of basic research findings, Dr. Duchaine believes that they will be diverse. "Besides forcing a reinterpretation of the function of the miR-17-92 proto-oncogene, it will prompt new potential therapeutic strategies. For example, the depth of the impact on the gene network in cells wherein miR-17-92 is amplified indicates a completely different gene network state. To me, this is a screaming opportunity for the testing of genotype-specific treatments in a precision medicine perspective."
-end-
"Oncogenic biogenesis of pri-miR-17~92 reveals hierarchy and competition amongst polycistronic microRNAs," by A. Donayo, T. Duchaine, et al, was published online June 26 in Molecular Cell. https://doi.org/10.1016/j.molcel.2019.05.033

McGill University

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.