The vast majority – approximately 80 percent – of our DNA does not code for proteins, yet it gets transcribed into RNA. These RNA molecules are called non-coding and fulfill multiple tasks in the cell. Alongside a well-studied group of small RNAs, there is also a class of so-called long non-coding RNAs consisting of more than 200 nucleotides.
Long non-coding RNAs regulate cellular processes such as cell cycle, growth and cell death. Therefore, it came as no surprise that many of these controlling molecules are linked to the progression of cancer. An example is the non-coding RNA MALAT1, which is considered a marker for disease progression in various forms of lung cancer: "The more MALAT1 tumor cells produce, the higher the odds for metastasis and a very unfavorable course of the disease," says Dr. Sven Diederichs, who discovered the molecule as part of his doctoral thesis. Diederichs now leads a junior research group at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Institute of Pathology of Heidelberg University.
In his current project, Diederichs has investigated the actual mechanisms used by MALAT1 to interfere in cellular processes and to promote metastasis. Diederichs and his team recently developed a method for selectively silencing long non-coding RNAs in the cell. To do so, the researchers integrate signaling sequences into the DNA which cause RNA transcripts to be broken down immediately after being formed. Then they analyze resulting changes in cellular biology.
For the first time, Diederichs and his team have been able to achieve almost complete silencing of MALAT1 in lung cancer cell cultures. In the modified cells they found that MALAT1 regulates numerous genes involved in metastasis. As a result, MALAT1-deficient tumor cells have impaired mobility and are less capable of invading surrounding tissue. When implanted in mice, they formed considerably less tumor nodules in the animals' lungs than cancer cells with intact MALAT1.
Encouraged by this result, the investigators explored whether it is also possible to block MALAT1 and thus prevent metastasis in an intact organism. In collaboration with ISIS Pharmaceuticals, Inc., the Heidelberg scientists developed short nucleic acid strands (antisense oligonucleotides) which are taken up by the cells and specifically block RNA molecules.
In mice injected with human lung cancer cells, MALAT1-specific antisense strands successfully inhibited metastasis formation. The animals' lungs showed fewer and smaller tumor nodules than those of control animals that had not been given the substance.
"Ten years after we discovered MALAT1 as a predictive marker in lung cancer, we now understand how this non-coding RNA influences metastasis. Moreover, this RNA has turned out to be a potential target for an innovative treatment with antisense RNAs." Diederichs and his team will further investigate this promising approach aiming to eventually prevent lung cancer from spreading.
Tony Gutschner, Monika Hämmerle, Moritz Eißmann, Jeff Hsu, Youngsoo Kim, Gene Hung, Alexey Revenko, Gayatri Arun, Marion Stentrup, Matthias Groß, Martin Zörnig, A. Robert MacLeod, David L. Spector, Sven Diederichs: The non-coding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Research 2013, DOI: 10.1158/0008-5472.CAN-12-2850
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
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