Long, Noncoding RNA Linked to Lung Cancer Metastasis

A recent paper described the functional significance of the long, noncoding RNA (lncRNA) MALAT1 in the process of lung cancer metastasis.

The vast majority of RNA molecules are transcribed by DNA segments that do not code for proteins. These RNAs, which arbitrarily have been defined as containing more than 200 nucleotides, are called long, noncoding RNAs and are clearly differentiated from small, inhibitory RNAs such as short, inhibitory RNA (siRNA) and microRNA (miRNA).

MALAT1 (metastasis associated lung adenocarcinoma transcript 1) also known as NEAT2 (noncoding nuclear-enriched abundant transcript 2) is a large, infrequently spliced noncoding RNA. This molecular species is expressed in the nucleus and is highly conserved among mammals. It is associated with metastasis, and positively regulates cell motility via the transcriptional and/or post-transcriptional regulation of motility-related genes.

To study the role of MALAT1 in metastasis investigators at the German Cancer Research Center (Heidelberg) developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases that destroyed molecules of MALAT1 as soon as they were manufactured. In this manner, the investigators were able to silence MALAT1 expression by reducing the level of this molecular species in lung cancer cells by more than 1,000-fold.

The investigators reported in the December 14, 2012, online edition of the journal Cancer Research that the MALAT1-deficient cells were impaired in migration and formed fewer tumor nodules in a mouse xenograft.

Mice that had been injected with human lung cancer cells were treated with antisense oligonucleotides directed at MALAT1. This treatment prevented metastasis formation after tumor implantation. The animals' lungs showed fewer and smaller tumor nodules than those of control animals that had not been given the antisense nucleotides.

"The more MALAT1 tumor cells produce, the higher the odds for metastasis and a very unfavorable course of the disease," said senior author Dr. Sven Diederichs, a group leader in molecular RNA biology and cancer at the German Cancer Research Center. "Ten years after we discovered MALAT1 as a predictive marker in lung cancer, we now understand how this noncoding RNA influences metastasis. Moreover, this RNA has turned out to be a potential target for an innovative treatment with antisense RNAs."

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German Cancer Research Center