Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells.
BACKGROUND & AIMS
Accumulating data from epidemiological and experimental studies have suggested that retinoids, which are vitamin A derivatives, exert antitumor activity in various organs. We performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs) to identify the genes facilitating the antitumor activity of retinoic acid (RA) and investigated their clinical significance in hepatocellular carcinoma (HCC).


METHODS
In silico analysis of RAREs was performed in the 5-kb upstream region of EST clusters. Chromatin immunoprecipitation analysis of the retinoic acid receptors and gene expression analysis were performed in HuH7, HepG2, and MCF7 cells treated with all-trans RA (ATRA). mRNA expression of RA-responsive genes was investigated using tumor and non-tumor tissues of clinical HCC samples from 171 patients. The association between gene expression and survival of patients was examined by Cox regression analysis.


RESULTS
We identified 201 candidate genes with promoter regions containing consensus RARE and finally selected 26 RA-responsive genes. Of these, downregulation of OTU domain-containing 7B (OTUD7B) gene, which was upregulated by ATRA, in tumor tissue was associated with a low cancer-specific survival of HCC patients. Functional analyses revealed that OTUD7B negatively regulates nuclear factor κB (NF-κB) signaling and decreases the survival of HCC cells.


CONCLUSIONS
We identified RA-responsive genes which are regulated by retinoid signal and found that low-OTUD7B mRNA expression is associated with a poor prognosis for HCC patients. OTUD7B-mediated inhibition of NF-κB signaling may be an effective target for antitumor therapy for HCC.
['Kanki|Keita|K|', 'Akechi|Yuji|Y|', 'Ueda|Chisa|C|', 'Tsuchiya|Hiroyuki|H|', 'Shimizu|Hiroki|H|', 'Ishijima|Naoki|N|', 'Toriguchi|Kan|K|', 'Hatano|Etsuro|E|', 'Endo|Kanenori|K|', 'Hirooka|Yasuaki|Y|', 'Shiota|Goshi|G|']
D000970:Antineoplastic Agents D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002470:Cell Survival D015536:Down-Regulation D010450:Endopeptidases D052138:Genes, Neoplasm D006801:Humans D008113:Liver Neoplasms D016328:NF-kappa B D011379:Prognosis D020218:Response Elements D015398:Signal Transduction D014212:Tretinoin
Hepatocellular carcinoma Hepatocellular carcinoma Retinoid retinoic acid retinoic acid response element RARE RA HCC EST chromatin immunoprecipitation retinoic acid receptor ATRA OTU domain-containing 7B OTUD7B NF-κB CYP26A1 ChIP Chemoprevention DR5 RAR RT-PCR RXR TRRA all-trans retinoic acid cytochrome P450 family 26A1 direct repeat 5 expression sequence tag hepatocellular carcinoma nuclear factor kappa B retinoid X receptor reverse transcription-polymerase chain reaction siRNA small-interfering RNA target RNA of retinoic acid