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)

Performance of different biomarkers for the management of hepatocellular carcinoma

“…Depending on the length, ncRNAs could be classified into short or long ncRNAs with an arbitrary size cut-off at 200 bases of length, being the most known (a) the long-ncRNA (lncRNA) and (b) the microRNA (miRNA). lncRNAs function take place by different molecular mechanisms such as interactions with DNA, RNA and proteins and can be classified into oncogenic or tumor suppressive genes [93][94][95][96][97][98] . Besides lncRNAs, miRNAs are endogenous small RNAs molecules with 20-25 bases of length.…”

circRNA meets gene amplification

“…These CNVs have been found to play a role in the tumorigenesis of a number of cancers including lung cancer (3). Most previous research has investigated the gain of oncogenic proteins, such as MYC (4), or the loss of tumor suppressors, such as PTEN (5), however, oncogenic proteins represent only a small portion of the genomic regions exhibiting CNV. While protein coding genes occupy less than 5% of the genome, more than 50% of the genome is transcribed (6).…”

“…While protein coding genes occupy less than 5% of the genome, more than 50% of the genome is transcribed (6). The non-coding portion of the transcriptome has been gaining increasing attention as numerous studies have implicated non-coding RNA in the development and regulation of cancer (5), and, as the majority of the transcriptome, non-coding RNAs represent a tremendous area of unexplored opportunities.…”

Focal loss of long non-coding RNA-PRAL, as determinant of cell function and phenotype of hepatocellular carcinoma

“…Recently Dr. Zhou and collaborators published an interesting paper in which they consider the opportunity to evaluate the outcome of HCC based on the loss of the lncRNA-PRAL, a p53 regulation associated lncRNA (16).…”