Researchers from the Duke-NUS Medical School in Singapore have shed light from their study on the role of long non-coding RNAs in the development of pancreatic cancer, bringing potential to new targets for precision medicine.
Long non-coding RNA molecules that do not get translated into proteins long been a mystery of the human genome. Scientists at Duke-NUS Medical School have found a way to systematically investigate their functions and discovered some could play a role in pancreatic cancer. Their findings, published in the journal Genome Medicine, highlight the importance of investigating long non-coding RNAs (lncRNAs) in living organisms.
In the central dogma of molecular biology, DNA codes for RNA, which, in turn, codes for protein. It is found that of the three billion bases in the human genome, only two percent encode proteins. Much of the remaining 98 percent of the genome are non-coding, and once thought to be the ‘dark matter’ of the human genome, with no known functions. Some lncRNAs, a major component of this genomic ‘dark matter’, have been shown to play key roles in diverse biological processes, ranging from development to diseases.
“By combining several advanced tools, we were able to investigate the role and function of ‘the dark matter that matters’ in pancreatic cancer,” said the study’s lead author, Mr Liu Shiyang, who is an MD/PhD student at Duke-NUS Medical School
Specifically, the research team wanted to identify lncRNAs that were regulated by a well-known pathway called Wnt signalling. This pathway regulates many genes that code for proteins, but its influence on lncRNAs has been unclear. Wnt signalling is known to fuel the growth of some pancreatic cancers. Turning off this pathway could not only help treat pancreatic cancer but also help researchers identify the parts of the genome that are regulated by it.
To do this, the research team turned to ETC-159, a made-in-Singapore Wnt-suppressing drug jointly developed by Duke-NUS and the Agency for Science, Technology and Research (A*STAR), which is currently progressing through clinical trials as a treatment for a range of cancers, including pancreatic.
The scientists compared what happened to lncRNAs when ETC-159 turned off Wnt signalling in preclinical model of pancreatic cancer and in normal pancreatic cancer cells cultured in the laboratory. By comparison, turning off Wnt signalling altered the expression of 1,503 lncRNAS while in normal pancreatic cancer cells only half that number of lncRNAs were altered. The researchers shared that this highlights the importance of studying lncRNAs within the context of a more natural environment.
The team then used the gene editing tool CRISPR to study what happened when the 1,503 Wnt-regulated lncRNAs were turned off in the preclinical model and in pancreatic cell cultures. Out of these studied, 21 lncRNAs were found to be able to modify pancreatic cancer cell growth in the living model, whereas only half that number were identified in the cancer cell culture tests.
“Our study provides a unique window in the largely unknown role of the dark matter of the genome that plays a functional role in pancreatic cancer, and will be a valuable resource for the scientific community studying Wnt-regulated lncRNAs in cancer,” said Professor David Virshup, director of Duke-NUS’ Cancer and Stem Cell Biology Programme, a senior co-author of the study.
Professor Virshup’s seminal research on Wnt signalling led to the development of ETC-159. “Understanding that a subset of Wnt-regulated lncRNAs can act as mediators of the oncogenic function of Wnt signalling in cancers provides potential new targets for precision cancer therapies.” He added.
Associate Professor Enrico Petretto, from Duke-NUS’ Cardiovascular and Metabolic Disorders Programme, also a senior co-author of the study, said, “Compared with previous studies we identified twice as many lncRNAs in vivo than what you might detect in vitro, and many of these are important for cancer cell growth only in vivo, providing important clues for the development of more effective cancer treatments.”
The research team called for further studies to understand how these Wnt-regulated lncRNAs regulate cancer cell proliferation.