Among the many discoveries resulting from the Human Genome Project, completed in 2003, is the fact that most human genes do not generate RNAs that encode proteins—in fact, only about 5% do so. This is a class that became known as junk DNA and that, during the last two decades, has been left aside when it comes to the treatment of diseases such as cancer.
If, until now, the major therapeutic targets have been messenger RNAs (which serve as a template for protein synthesis), nowadays researchers are getting closer and closer to discovering that these non-coding RNAs can, indeed, have important functions. This is the case of a study recently published in the journal Cellular Oncology, which concluded that long non-coding RNAs (lncRNAs) may play a role in pancreatic cancer.
The work —which was supported by Fapesp (projects 13/13844-2, 13/13350-0, 14/03943-6 and 19/04420-0) and was carried out by a multidisciplinary team composed of biochemists, molecular and cellular biologists , bioinformatics and physicians— analyzed a set of lncRNAs in pancreas tumor cell lines and used specific tools in the laboratory to manipulate their gene expression. The result was confirmation of its oncogenic character, that is, its expression favors the formation of tumors.
“We noticed that, by silencing the lncRNAs, the characteristics of the tumor cell were reduced and it became less aggressive and malignant because it proliferated less, migrated less, invaded less and did less DNA repair”, says Eduardo M. Reis, professor at the Department of Biochemistry at IQ-USP (Institute of Chemistry at the University of São Paulo).
According to the researcher, these results advance the understanding of pancreatic cancer, which, despite not having as high an incidence as other types of tumors, is lethal and has more limited treatment options.
“Since the study of molecular biology began and the use of new generation sequencing tools to identify new markers, many tumors have had better treatments, which have had a very positive impact on survival, for example, of patients with breast, lung and prostate”, says Reis. “Unfortunately this was not the case with pancreatic cancer.”
The next step now is to manipulate and silence the activity of these long non-coding RNAs in in vivo tumor models, in which tumor fragments from patients are implanted and maintained in mice (xenotumors). The goal is to confirm whether it is possible to reduce, in fact and in practice, the aggressiveness of the tumor.
In parallel, in addition to tumor fragments, researchers working with Reis also analyze single-cell RNA-Seq (single-cell RNA-Seq) sequencing databases. With this type of analysis, it is possible to obtain the transcriptome (set of transcribed RNAs) of each of the cells that make up a tissue, instead of looking at the tissue as a whole. The idea is also to verify the activity of these lncRNAs in the different cell types that make up the tumor microenvironment and, in this way, deepen the understanding of their functions and possibilities of use as a biomarker.
“Tell me who you hang out with…”
In addition to the aspect most applied to the treatment of pancreatic cancer, the study led by Reis contributes with a strategy to unravel the mechanism of action of non-coding RNAs. It is known that they are increased in the tumor and that, when manipulated, they have an effect on the cell. However, it is still not understood exactly how this happens. Unlike messenger RNAs, whose function can be predicted from the protein encoded in their sequence, with lncRNAs this is not yet possible.
“It’s more or less like when archaeologists and researchers found Egyptian hieroglyphics in an absolutely unknown language and didn’t have the Rosetta Stone to translate and understand them”, explains Reis. “For these lncRNAs, we still don’t know the code that translates the information contained in their primary sequence into a three-dimensional structure capable of performing specific functions.”
To circumvent this limitation, the researchers used a bioinformatics approach in which the activity of these non-coding RNAs is evaluated in the context of a co-expression network, along with the activity of other protein-coding genes whose function is already known. Comparing tumors and non-tumor samples, it was found that several non-coding RNAs present a pattern of co-expression similar to that of coding genes with important functions in the context of cancer. The following hypothesis was then generated in the style “tell me who you hang out with and I’ll tell you who you are”: if RNAs have the same pattern, then they can perform the same activities or be subject to the same regulation.
This is how, in the study, it was found that the lncRNA UCA1 is specifically required for DNA repair in tumor cells exposed to ionizing radiation. That is, the expression of this non-coding RNA apparently helps the tumor to recover from the damage caused by radiotherapy treatment.
According to the researcher, the study contributes with a relevant catalog of possible molecular functions of oncogenic lncRNAs that can help to expand the possibilities of studying the function of non-coding RNAs in pancreatic cancers and, consequently, lead more researchers to explore the development of new therapeutic options.
The article Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma can be read at: https://link.springer.com/article/10.1007/s13402-022-00678-5.
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