Effects Of Copy Number Variation Associated Long Non-coding RNA In Hepatocellular Carcinoma And Its Related Mechanisms

Hepatocellular carcinoma (HCC), one of the most common malignant human cancers worldwide, is identified as the third leading cause of cancer-related deaths. The most important risk factor for liver cancer is hepatitis virus infection and most cases in China were attributable to persistent hepatitis B virus (HBV) infections. The epidemiological surveys found that HBV-related HCC had familial aggregation and genetic susceptibility, what indicates that hepatocellular carcinogenesis can result from the genetic alterations. Therefore, it’s important to study the origination and susceptible mechanisms of HCC related to genome-wide abnormalities. Recurrent genome copy number aberrations are known to be a hallmark of cancers, including hepatocellular carcinoma, and chromosomal aberrations often lead to critical deregulations in gene expression, structure and function. Somatic DNA copy number variations (CNVs) associate with HCC occur on many genes associated directly or indirectly with signaling pathways operating in HCC development and progress. However, at the chromosomal breakpoints, protein-coding genes cannot always fully explain the tumorigenesis, indicating the importance of the non-coding transcripts, particularly long non-coding RNAs. Though lncRNAs do not possess protein-coding capacity, they have been implicated in a variety of important biological processes, including genomic imprinting during embryonic development, regulating the cell proliferation, differentiation and metastasis and even carcinogenesis of variety of tumors. It will be important and necessary to take a research on the relationship between genomic aberrations and lncRNAs in HCC.Here we performed an association analysis of lncRNAs expression and genome copy number aberrations in HCC to identify lncRNAs who were amplified or deleted in HCC. Of these, lncRNA-PRAL (P53Regulation Associated LncRNA) was often down-expressed with recurrent genomic copy number deletion, and the deletion of lncRNA-PRAL was associated with decreased recurrence-free survival in HCC patients. Additionally, our results reveals that HBV infection can decrease lncRNA-PRAL expression cooperating with genome copy number deletion in HCC and non-HCC patients. Further studies showed that lncRNA-PRAL could promote HCC cancer cell apoptosis in vitro and in vivo. Moreover, we found that lncRNA-PRAL facilitated the bond of HSP90and p53to enhance the nuclear import of p53. Thus, our findings indicate that chromosome deletion of lncRNA-PRAL is a crucial stimulus for tumour initiation and growth of HCC. While copy number variations associated lncRNAs play an important role in hepatocellular carcinogenesis, our studies could enrich the underlying mechanisms of HCC resulted from the genomic aberrations and strengthen the relationship between genetic and epigenetic regulations. And the data indicate that there is a complex network for lncRNAs in HCC.