Non-Coding Regions Of The Genome Could Play A Surprising Role In Cancer

Non-coding regions of the genome appear to be overexpressed in certain cancers, and could provide a novel therapeutic target

Only 2% of the human genome actually codes for proteins, while the rest is currently classified as 'non-coding'. While we once believed this had no function at all, many new theories and evidence are suggesting that this non-coding DNA may actually perform important functions - ranging from the creation of new genes and regulating existing ones. Non-coding DNA is translated into many different types of RNA, but the most prevalent is long non-coding RNAs, or lncRNAs. We know the human genome has around 16,000 of these but we still don't now what they do. 

"Since so much of the genome is being transcribed into RNA, it would seem that there would be a vast wealth of potential therapeutic targets out there that have not really been studied"

Could lncRNAs aid cancer growth?

In the latest study, a team of researchers at Cold Spring Harbor analysed a large variety of non-coding RNAs in breast cancer tissue to ascertain whether any were expressed at unusual levels. Many in fact were. This builds on previous research that has indicated non-coding RNA contributes to leukaemia and prostate cancer too. Indeed, in early 2016 it was shown that a particular lncRNA named Malat1 played a key role in regulating breast cancer progression. Stopping Malat1 expression actually inhibited metastasis, which shows how important these non-coding RNAs could actually be in cancer formation and growth.

After trawling through a huge database, the team arrived at several hundred lncRNAs that were expressed in 2 types of breast cancer in mice: luminal B and Her-2 positive. When they narrowed this down even further they isolated a group of critical 30 Mammary Tumor Associated RNAs, or MaTARs. 

Top: a luminal B breast cancer organoid before treatment (left), and after treatment with an antisense molecule (ASO) (right). In the next 3 rows different ASOs were applied to target 3 different long non-coding RNAs overexpressed in the breast cancer type. Overall, ASO#7, targeting MaTAR16, is most effective in shrinking a "metastatic" organoid while also changing its surface appearance from bulbous to smooth. Credit: Stephen Hearn, CSHL.

Does eliminating MaTARs diminish cancer? 

In collaboration with Ionis Pharmaceuticals the team then created so called 'anti-sense' molecules which are essentially opposites of their target RNAs - binding them tightly and leading to degradation. They then applied these to small 3-D organoids of cancerous mammary tissue they had created. When they successfully blocked 20 of these 30 MaTARs they found that cell proliferation, migration and invasion capabilities were actively inhibited. 

"We now have an innovative way of destroying RNA targets inside live cells and assessing whether a tumor is dependent on them for survival. We think these tests will have particular relevance for personalized medicine. We imagine a situation where organoids can be derived from an individual's tumor, grown up in a dish, and act as a platform for figuring out which antisense molecules comprise the optimal treatment for a patient"

Following the success in the laboratory, the next step is to move into mice directly. If this proves additionally successful then pre-clinical human trials may be on the horizon. The research reminds us how easy it is to overlook unknowns in biology; many scientists dismissed non-coding regions in the past, but its emerging that they play a complex, but far more critical role than we first imagined. Understanding non-coding DNA should therefore be a higher priority target in the future. 

Read more at MedicalXpress