Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma
Xiang Yi Kong, Erik Sebastian Vik, Meh Sameen Nawaz, Natalia Berges, Tuva B. Dahl, Cathrine Broberg Vågbø, Rajikala Suganthan, Filip M. Segers, Sverre Holm, Ana Quiles‐Jiménez, Ida Gregersen, Cathrine Fladeby, Pål Aukrust, Magnar Bjørås, Arne Klungland, Bente Halvorsen, Ingrun Alseth
Abstract
Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV-/- tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV-/- livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV-/- tumor suppressive phenotype calls for related studies in human HCC.