The overexpression of adenosine deaminases acting on RNA 1A (ADAR1) leads to the aberrant editing of the Kip1 ubiquitination-promoting complex 1 (KPC1) mRNA, causing the activation of the NF-κB signaling pathway and disease progression of intrahepatic cholangiocarcinoma (iCCA). This is according to the results of a new study published in the Journal of Experimental & Clinical Cancer Research. These results suggest that the ADAR1-KPC1-NF-κB axis could be a potential therapeutic target in iCCA.

Aberrant RNA editing is known to be linked to a number of cancer types. However, its role in iCCA is not well understood, the authors noted.

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In the present study, a team of researchers from China searched for dysregulated RNA editing that may be associated with iCCA through a whole-exome and transcriptome sequencing analysis.

The team first validated putative RNA editing sites using Sanger sequencing. They then assessed the effects of the KPC1 gene and its editing on the growth and metastasis of iCCA cells as an example using in vitro and in vivo experiments. Finally, using molecular methods, they investigated the potential crosstalk between KPC1 RNA editing and NF-κB signaling.

The results showed that there was an ADAR1-mediated over-editing pattern in intrahepatic CCA and that ADAR1 was often amplified and overexpressed in iCCA. 

“Notably, we identified a novel ADAR1-mediated A-to-I [adenosine-to-inosine] editing of KPC1 transcript”, which results in substitution of methionine with valine at residue 8,” the researchers wrote.  This substitution leads to the dysfunction of the KPC1 protein, which normally functions as a tumor suppressor through the NF-κB signaling.

“This study identified a collection of nonsynonymous RNA editing events in iCCAs,” the researchers wrote. “The importance of the ADAR1-KPC1-NF-κB axis in the development of iCCA suggested new application prospects in [the] treatment of this malignancy”.

Reference

Gao C, Zhou G, Shi J, et al. The A-to-I editing of KPC1 promotes intrahepatic cholangiocarcinoma by attenuating proteasomal processing of NF-κB1 p105 to p50. J Exp Clin Cancer Res. Published online December 8, 2022. doi:10.1186/s13046-022-02549-1