Weakened RNA interference reduces survival in ovarian cancer

December 17, 2008

Levels of two proteins in a woman's ovarian cancer are strongly associated with her likelihood of survival, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Dec. 18 issue of the New England Journal of Medicine.

The study shows that women with high levels of Dicer and Drosha, two proteins that are vital to a cell's gene-silencing machinery, had a median survival of 11 years. For those with low levels of either or both proteins, median survival was 2.66 years.

"Dicer and Drosha are crucial for two types of RNA interference, which cells use to shut down genes. We've found that when this machinery is disrupted, patient outcomes are poor," said senior author Anil Sood, M.D., professor in the departments of Gynecologic Oncology and Cancer Biology at M. D. Anderson. The study is the largest and most comprehensive demonstration of the connection between RNA interference and cancer.

The researchers also analyzed gene expression data in groups of lung and breast cancer patients and found similar associations with patient survival.

"Very consistently, we found that low levels of Dicer in particular are predictive of poor outcomes," Sood said. Molecular details of the raised risk for patients remain to be discovered, but it is likely that low levels of Dicer and Drosha permit some genes to continue functioning when they should be silenced.

"RNA interference has only been known for about a decade. The components of the machinery, what it does in cancer, and how it affects outcomes and therapy are not fully known," Sood said.

Potential clinical applications include using levels of the proteins as prognostic indicators to guide treatment decisions and eventually to exploit RNA interference to attack tumors, Sood said.

Interfering with gene expression

The team measured expression levels of Dicer and Drosha in 111 invasive ovarian cancer tumors and then compared the results to the patients' clinical outcomes. The initial findings were supported by a second analysis of gene expression in a different group of 132 ovarian cancer patients.

Analysis of 91 patients with lung cancer and 129 breast cancer patients reached similar conclusions, however, only Dicer levels were found to affect survival.

Drosha and Dicer are involved in the production of short interfering RNA (siRNA) and micro interfering RNA (miRNA). Genes express messenger RNA to tell a cell's protein-making machinery what protein to make. SiRNA and miRNA work by either cleaving the target messenger RNA or preventing protein production.

Drosha prepares pre-miRNA in the nucleus so it can be ejected into the cell's cytoplasm, where Dicer chops it into workable pieces of miRNA. Separately in the cytoplasm, Dicer cuts double-stranded RNA into bits of siRNA. Both miRNA and siRNA must go through Dicer to function naturally in the cell. Therapeutic pre-processed siRNA does not require Dicer and can be introduced into the cells as potential treatment, Sood noted.

Statistical analysis of five risk factors for ovarian cancer showed that only low Dicer levels, high-grade tumors and poor response to chemotherapy are independent predictors of survival. "When we find a new prognostic factor for cancer, we conduct a multivariate analysis to make sure that it's not associated with known factors, such as tumor grade. In this case, low Dicer levels were completely separate from traditional predictive factors," Sood said.

A genetic analysis of the Dicer and Drosha genes turned up mutations in both, but none that were associated with high or low levels of the proteins.

siRNA's potential for treatment

Sood and colleague Gabriel Lopez-Berestein, M.D., professor in M. D. Anderson's Department of Experimental Therapeutics, are developing cancer drugs that deliver a siRNA via fatty nanoparticles to silence a specific cancer-causing gene.

"We've found that another type of RNA, short hairpin RNA (shRNA) silences genes in a stable manner rather than the transient effects attributed to siRNA," said study senior co-author Menashe Bar-Eli, Ph.D., professor of Cancer Biology. However, animal models showed that these longer shRNA fragments could not silence genes in some cells. The authors found that about half of ovarian cancer cells either had low levels of Dicer and Drosha or lacked one or both proteins altogether.

A functional test of Dicer and Drosha for the project showed that shRNA does not work well with low levels of Dicer. When Dicer is low, siRNA still works. "This suggests that for therapeutic purposes, siRNA might be the better option as we develop new treatments based on interfering RNA," said co-author Robert Coleman, M.D., professor of gynecologic oncology.

Source: University of Texas M. D. Anderson Cancer Center

Explore further: Researchers identify DNA repair enzyme as a potential brain cancer drug target

Related Stories

Researchers identify DNA repair enzyme as a potential brain cancer drug target

January 6, 2016
Rapidly dividing cells rely on an enzyme called Dicer to help them repair the DNA damage that occurs as they make mistakes in copying their genetic material over and over for new cells. UNC Lineberger Comprehensive Cancer ...

Cyclin D1 governs microRNA processing in breast cancer

November 29, 2013
Cyclin D1, a protein that helps push a replicating cell through the cell cycle also mediates the processing and generation of mature microRNA (miRNA), according to new research publishing November 29 in Nature Communications. ...

When oxygen is short, EGFR prevents maturation of cancer-fighting miRNAs

May 23, 2013
Even while being dragged to its destruction inside a cell, a cancer-promoting growth factor receptor fires away, sending signals that thwart the development of tumor-suppressing microRNAs (miRNAs) before it's dissolved, researchers ...

Transgenic mice ready to fight obesity—and more

April 25, 2013
Scientists at the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw investigate mice with a very precisely modified genome. Because it is possible to turn off the Dicer gene in adult mice, ...

Delivering RNA with tiny sponge-like spheres

February 27, 2012
For the past decade, scientists have been pursuing cancer treatments based on RNA interference — a phenomenon that offers a way to shut off malfunctioning genes with short snippets of RNA. However, one huge challenge ...

Research team identifies key process in embryonic neurogenesis

February 6, 2015
MicroRNA are the tiny non-coding RNA molecules that help determine whether genes are expressed or silenced. One particular microRNA—miR-107—plays a key role in early brain development, and perhaps in the development of ...

Recommended for you

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

Liquid biopsy results differed substantially between two providers

December 14, 2017
Two Johns Hopkins prostate cancer researchers found significant disparities when they submitted identical patient samples to two different commercial liquid biopsy providers. Liquid biopsy is a new and noninvasive alternative ...

Testing the accuracy of FDA-approved and lab-developed cancer genetics tests

December 14, 2017
Cancer molecular testing can drive clinical decision making and help a clinician determine if a patient is a good candidate for a targeted therapeutic drug. Clinical tests for common cancer causing-mutations in the genes ...

Newest data links inflammation to chemo-brain

December 14, 2017
Inflammation in the blood plays a key role in "chemo-brain," according to a published pilot study that provides evidence for what scientists have long believed.

One in five young colon cancer patients have genetic link

December 13, 2017
As doctors grapple with increasing rates of colorectal cancers in young people, new research from the University of Michigan may offer some insight into how the disease developed and how to prevent further cancers. Researchers ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.