Characterizing the role of the adenosine deaminase acting on RNA (ADAR) gene as a potential oncogene in lung cancer

Characterizing the role of the adenosine deaminase acting on RNA (ADAR) gene as a potential oncogene in lung cancer

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Pan-cancer studies have demonstrated the presence of widespread dysregulated RNA-editing patterns in cancer, of which adenosine-to-inosine (A-to-I) RNA editing plays a major role. Adenosine deaminase acting on double-stranded RNA (ADAR) catalyzes the deamination of A to I, which results in the translational machinery reading inosine as guanosine, therefore effectively creating A-to-G changes in the RNA. Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes.  We have shown that ADAR is overexpressed in most lung adenocarcinoma (LUAD) cells compared to normal bronchial epithelial cells. Using the TCGA we performed an unbiased analysis and found that high ADAR expression is associated with decreased progression-free survival and higher cumulative incidence of tumor recurrence in LUAD patients. Stable knock-down ADAR in LUAD cells suggest that ADAR is involved in LUAD cell migration and invasion. Subsequent microarray analysis found that FAK is one of the targets of ADAR, and further investigation revealed that ADAR stabilizes FAK transcript by directly binding and editing FAK RNA. We continue to work on ADAR-mediated RNA editing targets and pathways in LUAD.

Amin EM, Liu Y, Deng S, Chudgar N, Mayo MW, Tan KS, Sanchez-Vega F, Schultz ND, Adusumilli PS, Jones DR. ADAR promotes lung adenocarcinoma migration and invasion through stabilization of FAK. Sci Signal 2017;10:497

ADAR Models

A. Immunohistochemical analysis showing low and high ADAR expression in two representative stage I LUAD tumors. Scale bars, 100 mm (top) and 50 mm (bottom). B. Chromatograms of FAK transcripts in the indicated cells. Arrow, the site chr8:141,702,274. The percentage of edited FAK detected by Sanger sequencing. n = 3 biological replicates. C. Cumulative incidence of recurrence based on ADAR protein expression in 802 patients with stage I LUAD (Gray’s test, P = 0.016). GAPDH, glyceraldehyde- phosphate dehydrogenase.