NEW YORK (GenomeWeb) – Researchers at Memorial Sloan Kettering Cancer Center and the University of Virginia have found that the RNA-editing protein ADAR (adenosine deaminase acting on double-stranded RNA) acts as a facilitator of lung adenocarcinoma progression by stabilizing FAK, one of a subset of genes found in cell migration pathways.
Previous pan-cancer studies have demonstrated the presence of widespread dysregulated RNA-editing patterns in cancer, and the editing activity of ADAR has been shown to affect gene expression and function in different ways. However, the exact mechanism of increased ADAR expression and their downstream effectors in the progression of lung cancer remained unclear, the researchers noted in their paper published today in Science Signaling.
The FAK gene, meanwhile, normally codes for a protein that is involved in reorganizing the cytoskeleton to promote migration. FAK overexpression occurs in more than 20 percent of solid tumors and correlates with tumor progression. It is also a crucial regulator of cancer cell migration, invasion, adhesion, and tumor metastasis.
For their study study, the researchers analyzed samples from 802 stage I lung adenocarcinoma patients, and found that an increased abundance of ADAR at both the mRNA and protein level correlated with tumor recurrence and poor prognosis.
In order to examine the functional mechanisms of ADAR in lung adenocarcinoma cells, first author Elianna Amin and her colleagues knocked down ADAR abundance in lung adenocarcinoma cells, and found that reducing ADAR suppressed the cells' mesenchymal properties, migration, and invasion in cell culture.
In order to further elucidate the putative pathways through which ADAR promotes lung adenocarcinoma cell migration and invasion, the researchers performed microarrays on the cells and found FAK to be the most significantly differentially expressed and down-regulated by ADAR loss. ADAR increased FAK expression and activity, revealing a connection between ADAR-mediated cell migration and invasion and FAK signaling, the researchers noted.
Through molecular analysis and RNA immunoprecipitation experiments, the researchers then identified post-transcriptional ADAR-induced RNA stabilization as the cause behind FAK growth in cancer cells. ADAR bound itself to the FAK RNA transcript and edited a specific intronic site to stabilize the gene, prompting an activation of FAK mRNA signaling and increase in protein expression.
The team also found that pharmacological inhibition of FAK blocked ADAR-induced invasiveness of lung adenocarcinoma cells, adding that these findings may eventually lead to possible treatments for lung adenocarcinoma patients with a high abundance of ADAR.
"By identifying FAK as a novel ADAR-editing target, our work establishes a potential therapeutic strategy of targeting FAK to prevent metastasis in early-stage [lung adenocarcinoma] with high ADAR expression," the authors wrote.