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Molecular biologists reveal new insights into tumor progression



  The Genetics of Cancer
When viewed under a fluorescence microscope, the individual probes illuminate each RNA in a single cell. Using a color combination method, UD molecular biologist Mona Batish can distinguish which labeled RNAs are linear (yellow) and circular (green). Picture credits: Kathy F. Atkinson

Molecular biologist Mona Batish of the University of Delaware and associates at Harvard Medical School and the University of California at Los Angeles have identified a novel circular ribonucleic acid (RNA) that increases tumor activity in soft tissue and connective tissue tumors.

The discovery of this new genetic entity has the potential to improve the understanding of the genetics of cancer and how cancer is identified and treated.

The researchers recently reported in a recent publication in Cell Research a nature journal. Batish co-authored the team, which included Jlenia Guarnerio, senior author and assistant professor of biomedical sciences at UCLA and Cedars-Sinai Medical Center. Pier Paolo Pandolfi, endowed chair of medicine and professor of medicine and pathology at Harvard Medical School; and colleagues from Beth Israel Deaconess Medical Center of Harvard Medical School, Rutgers University and Aalborg University Hospital in Denmark.

A Word on Circular RNA

RNA is a single-stranded molecule produced by DNA ̵

1; the code of life – in our body. Messenger RNA (mRNA) acts as a messenger, transporting instructions from the DNA code to protein-making machines, thus determining the composition of proteins in a cell. Besides mRNA, there are many other types of RNA that do not carry code for proteins but perform other important functions in cells. In summary, these are referred to as non-coding RNAs.

In the 1970s, a new class of noncoding RNAs called circular RNA was discovered. Circular RNA (circRNA) was originally thought to be a virus because most RNA molecules are linear, which means that their genetic sequence always moves in the forward direction. In contrast, circRNA is circular, although it has the same genetic sequence as linear RNA.

"Under certain circumstances, RNA-processing systems can be tempted to believe that they should bind to the ends," said Batish, an assistant professor of medical and molecular sciences in the UD College of Health Sciences. "When this error occurs, it creates a backward loop in the genetic sequence of the RNA and then proceeds – much like when you get a kink in the middle of a necklace." This loop separates and remains as circular RNA in the cell.

For a long time, the researchers considered this error, known as back splicing, to be meaningless. When genome sequencing began in the 1990s, scientists began to find circular RNA in brain tissue and other tissues. By 2014 they found that circular RNA is important, and today there is a whole field in which circular RNA is considered to be a biomarker of disease, especially cancer.

According to Batish, the role of circRNA in tumor progression is unclear.

In this work, the researchers describe a new circRNA generated by a gene called Zbtb7a that occurs in soft tissue tumors such as mesenchymal tumors. In its linear form, this RNA forms a tumor-suppressing protein that stops the growth of cancer. However, as soon as the same RNA forms a circRNA (ie gets a "kink"), the circular RNA acts independently to make the tumor more active and to effectively silence the tumor-suppressing protein.

  Molecular biologists unveil new findings on tumor progression
UD molecular biologist Mona Batish begins with fixed human bone marrow stromal cells (Hs5), which are shown here magnified 100 times. Credit: University of Delaware

According to Batish, this is the first time that this type of antagonist, tumor-promoting role of circRNA has been demonstrated in conjunction with linear RNA with the same genetic sequence.

Theoretically, both RNA strands should perform the same job because they are from the same genetic material, but not.

Method aids in the validation of findings

To validate their findings, researchers had to determine whether it is a linear or circular RNA because they share the same genetic code. This is where Batish's expertise came into play.

"You do not see RNA per se, so you need to flag it," Batish said. "But if you label it with something that's sequence-specific, it's hard to tell if it's linear or circular because the genetic code looks the same."

Batish had previously worked on probes that "flash" each RNA into a single cell as a single bright spot under the fluorescence microscope to understand how biological systems work at the cellular level. She adapted this method to differentiate circular RNA from its linear RNA counterpart using a color combination method.

"Basically, it's like creating a pearl pattern on a necklace, say, the RNA we work with contains red. We know that circular RNA is just a closed circle of green beads We add probes for both red and green beads and then image them under a fluorescence microscope, "said Batish. "If we see a signal for red and green in the same place that appears in the sample as yellow (combination of green and red), we know that it is linear RNA, and if it does not have red, it must be circular RNA. "

Using this method, they were able to simultaneously visualize linear and circular RNA in a single cell.

"This is the first time that we have realized that RNA with the same genetic sequence can sometimes play two roles Englisch: bio-pro.de/en/region/stern/magazine/…2/index. This is both a cancer oppressor and a cancer enhancer, and this role reversal is at the RNA level, "Batish said. "The identification of this new genetic entity provides new opportunities to understand the genetics of cancer and the role of circRNA in cancer biology." be able to develop treatment protocols to clearly address the circular RNA, but leave the linear RNA alone. This could provide a way to target it to prevent the circular RNA from eliminating the cancer-suppressing effect in the body.

  Molecular biologists reveal new insights into tumor progression.
UD molecular biologist Mona Batish labels each of the RNA found in the Hs5 cells with various probes, shown here as dots, which illuminate under a fluorescence microscope. Credit: University of Delaware

So what's next for Batish?

While this research focused on connective tissue and soft tissue tumors or diseases such as mesenchymal tumors, Batish said that the technique developed in their laboratory could be applied to any cancer, because every cancer is circular RNA.

Batish plans experiments to see if what they have observed at the cellular level also occurs in tissue samples. The study of this expression in both healthy and diseased tissue would help her better understand the biosignature of circular RNA.

"If we can show that it persists in samples that are left out and not treated properly, this has a real value. This is because the circular RNA is expressed differently, which means that my lung has a different circular RNA is expressed as my brain and other tissues or organs, "said Batish.

If you look at the circular RNAs that a person has, you may be able to use these cancer markers to identify what type of cancer a person has instead of sending the patient to imaging or other tests. "

Batish also wants to to investigate whether tumor-borne circular RNA is present in cell signaling molecules known as extracellular vesicles, describing these vesicles as letters, FedEx packets that assemble and deliver cells to neighboring cells to tell them what's nearby There are packets that tell neighboring cells that everything is alright in their cell, and at the same time create a microenvironment in which the cancer can grow, "she said.

Because each cancer starts with a single cell, Batish wants to explore the role of circular RNA. Play in this message. It could be a way to understand how cell-to-cell communication is used by tumor cells.

She also wants to develop tools for live imaging of circular RNA in cells. In collaboration with Jeff Caplan, director of the Bio-Imaging Center at the Delaware Biotechnology Institute, Batish is exploring ways to insert a "tracking device" into the cell to track the signal in real time as a circular. RNA is formed.

"That would be really groundbreaking if we can do it," Batish said.


Promising circular RNA as a cancer biomarker


Further information:
Jlenia Guarnerio et al. Intragene antagonistic roles of protein and circRNA in tumorigenesis, Cell Research (2019). DOI: 10.1038 / s41422-019-0192-1

Provided by
University of Delaware




Quote :
Molecular Biologists Unveil New Findings on Tumor Progression (2019, September 12)
retrieved on September 13, 2019
from https://phys.org/news/2019-09-molecular-biologists-reveal-insights-tumor.html

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