US scientists found that levels of two proteins called Dicer and Drosher that are involved in shutting down genes were linked to a woman’s chances of surviving ovarian cancer and similar effects were also found in lung and breast cancer patients. Women with high levels of these proteins had a median survival of 11 years while women with low levels of both proteins only had a median survival rate of 2.7 years.

The study was the work of Dr Anil Sood, professor in the departments of Gynecologic Oncology and Cancer Biology at MD Anderson Cancer Center in Houston, Texas, and colleagues from other research centres in the US, and is published in the 18 December issue of the New England Journal of Medicine, NEJM.

Dicer and Drosher are important players in a process called RNA interference which shuts down genes inside cells. Sood and colleagues found that when this process stops, ovarian cancer patient outcomes are poor; they also found similar effects in lung and breast cancer patients. The study is thought to be the largest and most comprehensive example of the effect of RNA interference on cancer.

Sood said in a press statement that they consistently found low levels of Dicer in particular were predictive of poor outcomes, although exactly what is happening at the molecular level is still not clear. The researchers found that when Dicer and Drosher aren’t around, genes that should be turned off continue working.

“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,” said Sood.

Sood suggested that this work could lead to new approaches for prognosis and treatment, perhaps even exploiting RNA interference to attack tumors.

For the study, Sood and colleagues measured expression levels of Dicer and Drosher in 111 ovarian cancer tumors and looked for links to patient outcomes. They replicated the findings with another group of 132 ovarian cancer patients and also analysed 91 patients with lung cancer ans 129 with breast cancer and found similar results, except in their case only levels of Dicer appeared to affect survival.

They did a statistical analysis of five risk factors for ovarian cancer and found only three were independently predictive of survival: low levels of Dicer, high-grade tumors, and poor response to chemotherapy.

As Sood explained:

“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 and colleagues also did a genetic analysis of Dicer and Drosher and found mutations in both, but none of them were linked to high or low levels of the proteins.

They found that about half of ovarian cancer cells either had low levels of Dicer and Drosha or had one or both proteins totally absent.

Scientists already know that genes don’t work directly, they have to express their instructions through messenger RNA which carry the coded instructions that tell cells which proteins to make. Dicer and Drosher appear to work by producing short interfering RNA (siRNA) and micro interfering RNA (miRNA) which stop messenger RNA from doing their job either by chopping them into pieces (cleaving) or directly stopping the production of the protein they are coded for.

Drosha and Dicer appear to collaborate in this interference process: Drosha gets pre-miRNA ready in the nucleus, this is ejected into the cytoplasm inside the cell, where Dicer cuts it into workable bits of miRNA. Dicer also does something that does not involve Drosha: it cuts double stranded RNA into pieces of siRNA.

Before they can work as normal inside cells, it looks like both miRNA and siRNA have to go through the Dicer process, although Sood said that it might be possible to pre-process siRNA therapeutically, without Dicer, and this could be a potential treatment route.

The researchers also found that another type of RNA, called short hairpin RNA (shRNA), stopped gene expression in a more stable way than siRNA, but testing in animals showed these longer pieces of RNA did not work in all cells.

They also found, this time via functional tests of Dicer and Drosha, that shRNA does not work very well when Dicer levels are low, but siRNA does. Thus in terms of new treatments based on interfering RNA, it would seem that siRNA might be a better option, they suggested.

“Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer.”
Merritt, William M., Lin, Yvonne G., Han, Liz Y., Kamat, Aparna A., Spannuth, Whitney A., Schmandt, Rosemarie, Urbauer, Diana, Pennacchio, Len A., Cheng, Jan-Fang, Nick, Alpa M., Deavers, Michael T., Mourad-Zeidan, Alexandra, Wang, Hua, Mueller, Peter, Lenburg, Marc E., Gray, Joe W., Mok, Samuel, Birrer, Michael J., Lopez-Berestein, Gabriel, Coleman, Robert L., Bar-Eli, Menashe, Sood, Anil K.
N Engl J Med Volume 359, Number 25, pages 2641-2650, December 18, 2008.

Click here for Abstract.

Sources: NEJM.

Written by: Catharine Paddock, PhD