Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma

Abstract

Systemic analyses using large‐scale genomic profiles have successfully identified cancer‐driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in “protein‐coding gene desert” regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA‐PRAL (p53 regulation‐associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA‐PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem‐loop motifs at the 5′ end of lncRNA‐PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2‐dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA‐PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application. Conclusions: lncRNA‐PRAL, one of the key cancer‐driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy. (Hepatology 2016;63:850‐863)