Impact of PTEN expression on the outcome of hepatitis C virus-positive cirrhotic hepatocellular carcinoma patients: possible relationship with COX II and inducible nitric oxide synthase.
PTEN, a novel tumor suppressor, functions as a regulator of both cell cycle progression and apoptosis. PTEN gene is frequently mutated or deleted in several malignancies including human hepatocellular carcinoma (HCC). The clinical significance and prognostic value of PTEN expression in HCC or in the surrounding non-cancerous parenchyma remain obscure. Using immunohistochemistry, we analyzed the PTEN protein expression in 46 tissue sections collected from surgically resected hepatitis C virus (HCV)-positive cirrhotic HCC patients. Although the surrounding normal liver tissue was strongly expressing PTEN in 42 cases (91.3%), the immunostaining intensity was low in 29 (63.1%) and high in 17 (36.9%) of the HCCs. Additionally a significant positive correlation was identified between low PTEN expression in the HCC and increased expression of iNOS and COX II in the surrounding liver. The overall survival was significantly longer for the HCC-patients with high PTEN expression than patients with low PTEN expression. Univariate analysis revealed PTEN expression as an independent prognostic factor for patients survival. By Western blot analysis we also found that the Akt/PKB signaling, which is negatively regulated by PTEN, was upregulated in the HCCs in comparison to its expression in the surrounding liver tissue. These results demonstrate that downregulation of PTEN in the tumor is an important step in HCV-positive cirrhotic hepatocarcinogenesis and might result in concomitant upregulation of iNOS and COX II in the surrounding liver in favor of tumor promotion.
Second Department of Surgery, Shimane Medical University, Izumo, Japan. rahman@shimane-med.ac.jp
Mohammad Atiqur
MA
Rahman
Ioannis D
ID
Kyriazanos
Takashi
T
Ono
Akira
A
Yamanoi
Hitoshi
H
Kohno
Mikako
M
Tsuchiya
Naofumi
N
Nagasue
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D051546:Cyclooxygenase 2; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor; D016174:Hepacivirus; D006526:Hepatitis C / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000401:mortality / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015996:Survival Rate; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000378:metabolism
D007527:Isoenzymes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000509:alpha-Fetoproteins; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human