Multiple Copies of RNA Editing Enzyme Gene Promote Lung Cancer Growth

The copy-number gain for ADAR1 was associated with overexpression of the transcript and protein in lung cancer cell lines and primary tumors. Under these circumstances, ADAR1 exerted growth-enhancing activity in vitro and in vivo, as was demonstrated in depletion and transfection experiments in cell culture and mouse models.

From a functional standpoint, ADAR1 mediated the adenosine-to-inosine editing levels of coding (e.g., the NEIL1 or Nei-like DNA glycosylase 1 gene) and noncoding (miR-381) RNA transcripts. A high ADAR1 copy number was associated with poor outcome in early-stage lung cancer patients, which could be useful in the clinical management of these cases.

"We found that 5%–10% of lung tumors, instead of having the normal dose of a gene (two copies, one on the maternal chromosome and another in his father) have an overdose of the same, around 10 extra copies of the gene," said senior author Dr. Manel Esteller, professor of genetics at the Bellvitge Biomedical Research Institute.

"The ADAR1 gene regulates the level of mutations in RNA, and it is a publisher gene. People with an excess of this gene have an imbalance in the composition of this molecule just causing abnormal proteins that contribute to tumor growth. If we study these altered target genes we would not see mutations in their DNA, but we will see altered proteins because of these sequence alterations of the intermediate molecule, RNA."

"Graphically we could say that there has been a problem of 'Lost in Translation,'" said Dr. Esteller. "Now it will be important to know whether this type of alteration is common in the rest of human tumors, if it occurs significantly in other diseases, and if there is any way to use this knowledge to better treatment."

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Bellvitge Biomedical Research Institute