CDK13 RNA Over-Editing Mediated by ADAR1 Associates with Poor Prognosis of Hepatocellular Carcinoma Patients

Abstract

Background/Aims: Aberrant RNA editing, mediated by adenosine deaminases acting on RNA (ADAR), serves as a post-transcriptional event participating in tumorigenesis and prognosis. However, the RNA editing profiles during HCC progression and their clinical correlations remain unclear. Methods: Multiple tissue samples were collected from an advanced HCC patient. RNA-seq was performed to obtain the RNA editing profiles for each sample. Two RNA editing sites from CDK13 were further validated in 60 HCC patients; and their potential regulatory mechanisms were investigated. Results: In-depth analysis of the RNA-seq data revealed a significant number of editing sites (632-816) in coding regions for each tissue sample, showing branched evolution during tumorigenesis and metastasis. Two editing sites (Q103R and K96R) in CDK13 showed significant over-editing in tumor, and these phenomenon were validated in 60 HCC patients. Furthermore, the clinicopathological analysis revealed that these CDK13 over-editing sites were positively associated with TNM, PVTT and poor prognosis. In addition, the editing level of these sites were significantly correlated with the expression of ADAR1. Loss of function assays further proved that these CDK13 over-editing sites were mediated by ADAR1 in HCC cells. Conclusions: CDK13 RNA over-editing sites mediated by ADAR1 may serve as novel cancer driver events in HCC progression.

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma

“…Considering the important overall impact of RNA editing on cancer [15, 26–28], we asked whether inosinome might correlate with patients’ clinical parameters such as OS, age at diagnosis, or the Karnofsky Performance Score (KPS).…”

CDK13-Mediated Cell Cycle Disorder Promotes Tumorigenesis of High HMGA2 Expression Gastric Cancer

“…CDK13 had been paid close attention in the children with certain types of congenital heart defects, and the heterozygous missense mutations of CDK13 would impair magnesium ion binding to ATP in these pediatric sufferers, yet no further studies were performed (Bostwick et al, 2017;Uehara et al, 2018;Hamilton and Suri, 2019;Novakova et al, 2019). The role of CDK13 in cancers, such as ovarian cancer and hepatocellular carcinoma, has been focused on since 2018; however, no underlining mechanism has been reported (Dong et al, 2018;Zeng et al, 2018;Wang et al, 2019). TCGA database showed that CDK13 is amplified in different categories of cancer, indicating it could contribute to the tumorigenesis and development of cancer in humans.…”

Proline‐arginine poly‐dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA

“…In this series of experiments, we chose three different RNAs as substrates, Cdk13 , NICN1 , and NEIL1 . Cdk13 is canonically edited by ADAR1, resulting in Q103R amino acid substitution (Dong et al., 2018; Maas et al., 2011; Sakurai et al., 2014). More than 30 adenosine residues within the inverted repeat Alu sequence in a 3’ untranslated region (3’ UTR) of the NICN1 RNA have reported to be randomly edited (Bazak et al., 2014; Chen et al., 2008; Nishikura, 2016).…”