Nav: Home

Making 'sense' of the 'cart before the horse' in mammalian cells.

January 28, 2019

A fusion gene is a new gene made by joining parts of two different genes. The current thought is that fusion genes can happen in cells with unstable genome when part of the DNA from one chromosome moves to another chromosome. When the fusion gene is transcribed into RNA, the product is a fusion RNA that then is translated into a fusion protein. Fusion proteins may lead to cancer development. For instance, they are found in some types of cancer such as leukemia, prostate, breast, lung and others, and are being studied for the diagnosis and treatment of these diseases.

"According to this accepted notion, fusion genes precede fusion RNA, but some studies have raised doubts that this is always the case. In particular, cancer studies have reported the presence of fusion RNA in individuals in which the corresponding fusion gene cannot be detected," said corresponding author Dr. Laising Yen, associate professor of pathology & immunology and of molecular and cellular biology at Baylor College of Medicine.

To explain these findings, about 10 years ago scientists proposed the 'cart-before-the-horse-hypothesis,' which puts forward the idea that fusion RNA can form first and then guide the rearrangement of genes to form the corresponding fusion gene. Although this process has been found in simpler organisms such as the paramecium, studies have yet to come forward showing that this proposed RNA-mediate gene rearrangements also happen in mammalian cells. Until now.

"The Yen lab works on RNA, and one of our interests is to study it in relation to cancer, ovarian and prostate cancer specifically," said first author Dr. Sachin Kumar Gupta, postdoctoral associate in pathology at Baylor College of Medicine. "In this study, we investigated whether the cart could actually be before the horse. Can a fusion RNA induce the corresponding fusion gene?"

The researchers worked with prostate cancer cell line LNCaP, which lacks the fusion gene TMPRSS2-ERG found in 50 percent of prostate cancers. To test "the cart before the horse" hypothesis, Gupta and his colleagues expressed in LNCaP cells a short fusion RNA consisting of part gene TMPRSS2 and part gene ERG. If the short fusion RNA led to the formation of the fusion gene TMPRSS2-ERG, they expected to find evidence of the newly created fused gene both in the DNA genome and in the form of the full-length fusion RNA produced from that fusion gene.

Making sense of the 'cart before the horse'

"When we expressed the sense or coding short fusion RNA, we did not detect evidence that the fusion gene had been formed," Gupta said. "We then thought, why not try the antisense fusion RNA instead?"

Antisense RNA is an RNA strand with a sequence that is complementary to the one of a sense or coding RNA. Coding RNA is the one that is involved in the translation of genetic instructions into protein. In theory, the authors explain, antisense RNAs should bind to the same genome segment sense RNA binds, just to a different DNA strand, and could mediate gene rearrangements leading to the formation of fusion genes.

"We found that if we overexpress the short fusion RNA in the antisense orientation, but not in the sense orientation, we can induce gene fusion in a tissue culture setting in three days," Yen said. "We showed this for two different fusion genes."

"We were very surprised. This is a non-coding RNA for which we have shown a new function: it can induce the formation of fusion genes. The antisense RNA, not the sense RNA, is the cart before the horse," Gupta said.

The researchers also showed that this RNA-induced gene fusion can occur in non-cancerous, normal cells. Expressing antisense fusion RNA in normal prostate epithelial cell lines resulted in the formation of the corresponding fusion gene in these cells.

"Our study suggests an early stage mechanism for the formation of cancer fusion genes that provides a new perspective in cancer development," Yen said. "We have uncovered a second way by which gene recombination can happen. We propose that this process is mediated by RNA with sequences that are similar to, and antisense to, those of the joined genes."

Cancer fusion genes are important for therapy and biomarker development. Fusion genes also have a lot to say regarding how a normal cell begins to transform into a cancer cell. Therefore, the authors explain, understanding the mechanisms of fusion gene formation could lead to the development of treatments to prevent cancer.

The researchers would next like to investigate whether RNA-mediated gene fusion also can happen in other types of cancer and explore the molecular mechanism for diagnosis and therapy.
Interested in learning all the details of this work? Read it in the Proceedings of the National Academy of Sciences.

Dr. Liming Luo at Baylor College of Medicine also contributed to this work. Financial support was provided by the National Institutes of Health (grants R01EB013584, DK56338, and CA125123), the Cancer Prevention Research Institute of Texas (grants HIHRRA RP160795, RP150578, RP160283), the Pilot Grant from Dan L Duncan Comprehensive Cancer Center and the Dunn Gulf Coast Consortium for Chemical Genomics.

Baylor College of Medicine

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...