RNA editing by hydrolytic deamnation of adenosine (A) to inosine (I) is the most common type of editing, catalyzed by theADAR(AdenosineDeaminase that act on RNA) family. MicroRNAs (miRNAs) are small non-coding RNA molecules that block translation of partially complementary targets located in the 3`UTR of mRNAs, or guide the degradation of target mRNAs.
ADAR1 is silenced in various solid tumors, and we show that particularly in melanoma. Results from our lab show that this downregulation alters melanoma cell morphology, facilitates proliferation and cell cycle, and increases the tumorigenic potential of melanoma cells. We further found that ADAR1 controls the expression of more than a hundred cellular miRNAs.
Here we study several ADAR1-regulated miRNAs and their target genes, in the context of melanoma cell biology. Highest priority was given to miR-607, a miRNA with unknown roles that is predicted by TargetScan5.1 to target the mRNA of Sox2 in four different sites within the 3'UTR. Sox2 is an important transcription factor involved in the generation of inducible pluripotent stem cells. Importantly, ADAR1-knockdown cells show decreased miR-607 expression and increased Sox2 expression, suggesting that this might be an effector axis of ADAR1 in melanoma. Indeed, forced expression of miR-607 downregulates Sox2 at the protein level but not at the mRNA level, pointing it operates as a translational repressor. Phenocopy knockdown of Sox2 with selective RNAi inhibits melanoma cell proliferation, confirming this axis.
Planned studies will determine the role of RNA editing in this process, how miR-607 is controlled by ADAR1 and the physiological relevance by expression analyses in histopathological samples.
These findings deepen our understanding of central role of ADAR1 in cancer development and progression, which could be innovatively translated into various medical technologies.
