RNA molecule identified as a growth driver in various types of cancer

Over 75 percent of the human genome is translated into RNA, but only two percent of the genome codes for proteins. The non-protein-coding RNA molecules perform a variety of functional, regulatory or structural tasks in the cell.

Non-coding RNA molecules with a length of more than 200 nucleotides are called lncRNAs (long non-coding RNAs). In recent years, more than 10,000 different molecules of this class have been discovered and their number is constantly increasing. For a long time, they were not attributed a special function. However, scientists are increasingly recognizing that they play an important role in various biological processes.

Detailed analyses have shown that lncRNAs in cancer cells are often characteristically deregulated. They can act as cancer drivers by interfering with cellular processes that promote malignancy: for example, they influence viability, the ability to divide and migrate, programmed cell death or angiogenesis.

Scientists therefore regard cancer-typically deregulated lncRNAs as promising target structures for new therapeutic approaches. Sven Diederichs from the German Cancer Research Center (DKFZ) and the German Consortium for Tranlational Cancer Research (DKTK) in Freiburg has now started a targeted search for lncRNAs that might have a role in the development of liver cancer. Liver cancer is regarded as the fourth most frequent cause of cancer-related deaths worldwide: The number of new cases is increasing in many parts of the world, but treatment options are still limited.

Diederichs and his team sceened 200 liver cell cancer patient samples for lncRNAs that were strongly overrepresented in the cancer cells. During this investigation, the researchers discovered the lncRNA "lincNMR" (long intergenic noncoding RNA nucleotide metabolism regulator). In liver cancer cell lines, but also in breast and lung cancer cell lines, switching off lincNMR sometimes drastically slowed down the cell division rate and also accelerated cell aging.

In vivo experiments confirmed the researchers that cancer cells whose lincNMR was switched off grew into smaller tumors. For these investigations, the scientists used chorioallantoic membranes in incubated chicken eggs to avoid the use of laboratory animals.

The examination of tissue samples from numerous types of cancer, including bladder and cervical tumors and various forms of lung cancer, consistently showed that lincNMR is significantly overrepresented in the tumor - compared to healthy normal tissue.

In a detailed molecular characterization, Diederichs and his team found that lincNMR plays an important role in controlling the nucleotide metabolism of the cell. If lincNMR is switched off, the cell no longer has sufficient building blocks for DNA synthesis, and cell division is slowed down.
"Overall, our results suggest that lincNMR is an RNA molecule of broad relevance to various cancers. In many cases, cancer growth seems to depend on the availability of sufficient amounts of lincNMR to the cells. Therefore, RNA might also be an attractive target structure for new therapeutic approaches. We intend to further investigate this in future investigations," summarises Sven Diederichs.

Minakshi Gandhi, Matthias Groß, Jessica M. Holler, Si'Ana A. Coggins, Nitin Patil, Joerg H. Leupold, Mathias Munschauer, Monica Schenone, Christina R. Hartigan, Heike Allgayer, Baek Kim and Sven Diederichs: The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer.
Nature Communications 2020, https://doi.org/10.1038/s41467-020-17007-9