Introduction: Transarterial chemoembolization (TACE) is the commonly used therapy of unresectable hepatocellular carcinoma (HCC), though the prognosis of different TACE-treated HCC patients varies, which may be due to the heterogeneity of HCC tumors caused by genetic variants and epigenetic changes such as RNA editing. There is dysregulated RNA adenosine-to-inosine (A-to-I) editing in HCC and RNA-edited genes are involved in the epigenetic process. It remains unclear how genetic variants of RNA editing genes affect the prognosis of HCC cases treated by TACE.
Methods: In this study, we examined 28 potentially functional single-nucleotide polymorphisms (SNPs) of four RNA editing genes (ADARB1, ADAR, ADARB2 and AIMP2 ) in two independent TACE patient cohorts.
Results: We found that ADARB1 rs1051367 and rs2253763 polymorphisms were markedly associated with the prognosis of HCC cases who received TACE in both cohorts. In HCC cells, the rs2253763 C-to-T change in ADARB1 3’-untranslated region attenuated its binding with miR-542-3p and allele-specifically elevated ADARB1 levels. Consistent with this, patients carrying the rs2253763 C allele showed reduced ADARB1 expression in cancer tissues and notably shorter survival after TACE therapy in comparison with individuals with the T allele. Ectopic ADARB1 profoundly enhanced the efficacy of oxaliplatin, one of the common TACE chemotherapeutic drugs.
Discussion: Our findings highlighted the value of ADARB1 polymorphisms as prognostic markers in TACE therapy for HCC patients. Notably, our findings revealed that targeting the ADARB1 enzyme may be a promising therapeutic strategy in combination with TACE for HCC cases.
Keywords: RNA editing, ADARB1, hepatocellular carcinoma, genetic polymorphism, gene expression, drug sensitivity