Although expression of non-protein-coding RNA (ncRNA) can be altered in human 
cancers, their functional relevance is unknown. Ultraconserved regions are 
noncoding genomic segments that are 100% conserved across humans, mice, and 
rats. Conservation of gene sequences across species may indicate an essential 
functional role, and therefore we evaluated the expression of ultraconserved 
RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was 
analyzed with a custom microarray. Expression was verified in cell lines by 
real-time PCR or in tissues by in situ hybridization using tissue microarrays. 
Cellular ucRNA expression was modulated with siRNAs, and the effects on global 
gene expression and growth of human and murine HCC cells were evaluated. 
Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with 
nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for 
ultraconserved element 338 (uc.338), which was dramatically increased in human 
HCC compared with noncancerous adjacent tissues. Although uc.338 is partially 
located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed 
ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 
590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated 
predominant effects on genes involved in cell growth. These effects were 
experimentally demonstrated in both human and murine cells. siRNA to TUC338 
decreased both anchorage-dependent and anchorage-independent growth of HCC 
cells. These studies identify a critical role for TUC338 in regulation of 
transformed cell growth and of transcribed ultraconserved ncRNA as a unique 
class of genes involved in the pathobiology of HCC.