dUTP pyrophosphatase expression correlates with a poor prognosis in hepatocellular carcinoma.
BACKGROUND
Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis, partly owing to the lack of biomarkers that support its classification in line with its malignant nature. To discover a novel molecular marker that is related to the efficacy of treatment for HCC and its biological nature, we performed serial analysis of gene expression (SAGE) in HCC, normal liver and cirrhotic liver tissues.


METHODS
Gene expression profiles of HCC tissues and non-cancerous liver tissues were obtained by SAGE. Suppression of the target gene by RNA interference was used to evaluate its role in HCC in vitro. The relation of the identified marker and prognosis was statistically examined in surgically resected HCC patients.


RESULTS
We identified significant overexpression of DUT, which encodes dUTP pyrophosphatase (dUTPase), in HCC tissue, and this was confirmed in about two-thirds of the HCC samples by reverse-transcription polymerase chain reaction (n=20). Suppression of dUTPase expression using short interfering RNAs inhibited cell proliferation and sensitized HuH7 cells to 5-fluorouracil treatment. Nuclear dUTPase expression was observed in 36.6% of surgically resected HCC samples (n=82) evaluated by immunohistochemistry, and its expression was significantly correlated with the histological grades (P=0.0099). Notably, nuclear dUTPase expression correlated with a poor prognosis with statistical significance (HR, 2.47; 95% CI, 1.08-5.66; P=0.032).


CONCLUSIONS
Taken together, these results suggest that nuclear dUTPase may be a good biomarker for predicting prognosis in HCC patients after surgical resection. Development of novel dUTPase inhibitors may facilitate the eradication of HCC.
Takatori
Hajime
H
Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Yamashita
Taro
T
Honda
Masao
M
Nishino
Ryuhei
R
Arai
Kuniaki
K
Yamashita
Tatsuya
T
Takamura
Hiroyuki
H
Ohta
Tetsuo
T
Zen
Yoh
Y
Kaneko
Shuichi
S
D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase