Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA.
OBJECTIVE
Recent studies have highlighted the role of noncoding RNAs (ncRNAs) in carcinogenesis, and suggested that this class of genes might be used as biomarkers in cancer. We searched the human genome for novel genes including ncRNAs related to hepatocellular carcinoma (HCC).


METHODS
An HCC-specific gene library was generated and screened for deregulated genes with 46 HCCs, 4 focal nodular hyperplasias, and 7 cirrhoses utilizing cDNA arrays. Sequencing of library clones identified a novel ncRNA as the most up-regulated gene in HCC. This gene was also cloned from different monkeys and characterized by quantitative RT-PCR, Northern blot analysis and in situ hybridization. Structural and functional studies included comparative sequence and protein expression analyses, quantitative RT-PCR of polysomal preparations, and siRNA-mediated knockdown experiments.


RESULTS
The most up-regulated gene in HCC named highly up-regulated in liver cancer (HULC) was characterized as a novel mRNA-like ncRNA. HULC RNA is spliced and polyadenlyated, and resembles the mammalian LTR transposon 1A. It does not contain substantial open reading frames, and no native translation product was detected. HULC is present in the cytoplasm, where it copurifies with ribosomes. siRNA-mediated knockdown of HULC RNA in 2 HCC cell lines altered the expression of several genes, 5 of which were known to be affected in HCC, suggesting a role for HULC in post-transcriptional modulation of gene expression.


CONCLUSIONS
HULC is the first ncRNA with highly specific up-regulation in HCC. Because HULC was detected in blood of HCC patients, a potential use as novel biomarker can be envisaged.
Panzitt
Katrin
K
Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.
Tschernatsch
Marisa M O
MM
Guelly
Christian
C
Moustafa
Tarek
T
Stradner
Martin
M
Strohmaier
Heimo M
HM
Buck
Charles R
CR
Denk
Helmut
H
Schroeder
Renée
R
Trauner
Michael
M
Zatloukal
Kurt
K
D000595:Amino Acid Sequence; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000503:physiopathology; D017124:Conserved Sequence; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D008113:Liver Neoplasms / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D034741:RNA, Small Interfering; D022661:RNA, Untranslated / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D022661:RNA, Untranslated