Biological Function And Molecular Mechanism Of Non-coding RNA HULC In Promoting Cell Proliferation, Migration And Invasion

Non-coding RNAs (ncRNAs), which transcript from DNA but do not encode protein, contain high density of stop codons or lack extensive "Open Reading Frame". They have been shown to be involved in the different levels of cell regulations including chromosome modification, transcription regulation, RNA splicing and RNA stability, via RNA-RNA basepair, RNA-protein interaction, RNA-DNA interaction. Recently, dysregulated expressions of ncRNAs have been reported in many types of cancers, indicating that they maybe play critical roles in tumorigenesis.HULC (Highly Up-regulated in Liver Cancer), is an ncRNA characterized in hepatocelluar carcinoma (HCC). The HULC gene locates at 6p24.3 and the transcripts of this gene is spliced and polyadenylated like mRNA to form a 500bp RNA. Feature of the HULC RNA sequence is the high density of stop codons in the small potential reading frames and can not encode a protein product. HULC RNA can be detected in HCC tissues as well as in the blood of HCC patients at a high level. It has also been reported that HULC expression is not confined to HCC, but also to those colorectal carcinomas that metastasize to the liver. HULC RNA can therefore be used as specific molecular markers for HCC. However, little is known about the function of HULC RNA and its molecular mechanism.In the present thesis we firstly show that endogenously high expression of HULC RNA in HepG2 cell is not caused by gene amplification and the half-life of HULC RNA is approximately 6 hours. Meanwhile, HULC RNA can promote cell proliferation, migration and invasion in vitro and also inhibit cisplatin-induced apoptosis. Moreover, we have shown for the first time that HULC RNA can specifically bind to YB-1 protein both in vitro and in vivo. YB1 protein appears to carry out multiple functions, including the roles in transcriptional and translational regulation, RNA splicing and masking, DNA repair, and cell proliferation. Our study further demonstrates that HULC RNA can promote nuclear localization of YB-1 protein after DNA damage stress, and is involved in the transcriptional regulation of its target genes.