Inducible nitric oxide synthase and survivin messenger RNA expression in hepatocellular carcinoma.
OBJECTIVE
Proliferative activity and suppression of apoptosis of cancer cells are important to tumor progression in hepatocellular carcinoma (HCC). Recently, the expressions of inducible nitric oxide synthase (iNOS) and survivin mRNA have been reported to correlate with suppression of apoptosis in some tumors. However, the clinical importance of expression of these genes in HCC progression remains unclear. In the present study, the correlation between the expression of iNOS and survivin mRNA and the occurrence of spontaneous apoptosis and proliferative activity of cancer cells and prognostic importance of expression of these genes in HCC were investigated.


METHODS
Tissues were obtained by surgical resection of livers from 61 patients with HCC and 8 without HCC. Expressions of iNOS and survivin mRNA were evaluated using the reverse transcription-PCR in 61 tumors, 61 adjacent histologically noncancerous livers, and 8 normal livers. Apoptotic cancer cells and the proliferative activity of cancer cells were detected by immunohistochemistry.


RESULTS
iNOS mRNA expression was detected in 34 of 61 (55.7%) HCCs, 19 of 61 (31.1%) noncancerous liver tissues adjacent to carcinoma, and none of the 8 normal livers. In addition, survivin mRNA was detected in 19 of 61 (31.1%) HCCs, none of 61 noncancerous liver tissues, and none of the 8 normal livers. iNOS mRNA expression did not correlate with the proliferative activity of cancer cells or with the occurrence of apoptosis in HCCs. In contrast, survivin mRNA expression strongly correlated with a high proliferative activity of cancer cells and a low apoptotic index. Disease-specific survivals did not differ between patients with iNOS-positive or -negative HCCs. Although, the disease-specific survival of patients with survivin-positive HCCs was significantly poorer than that of patients with survivin-negative HCCs.


CONCLUSIONS
These results indicate that iNOS may not correlate with cancer cell-proliferative activity or apoptosis; survivin, however, may not only suppress apoptosis but also accelerate cancer cell-proliferative activity and play an important role in tumor progression in HCC.
Ikeguchi
Masahide
M
First Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan. masaike@grape.med.tottori-u.ac.jp
Ueta
Tsuyoshi
T
Yamane
Yoshiaki
Y
Hirooka
Yasuaki
Y
Kaibara
Nobuaki
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins; D009367:Neoplasm Staging; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000077022:Survivin; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077022:Survivin; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II