Ikeguchi Masahide, Ueta Tsuyoshi, Yamane Yoshiaki, Hirooka Yasuaki, Kaibara Nobuaki
First Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Clin Cancer Res. 2002 Oct;8(10):3131-6.
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.
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.
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.
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.
癌细胞的增殖活性和凋亡抑制对肝细胞癌（HCC）的肿瘤进展至关重要。最近，有报道称诱导型一氧化氮合酶（iNOS）和生存素mRNA的表达与某些肿瘤中的凋亡抑制相关。然而，这些基因的表达在HCC进展中的临床重要性仍不清楚。在本研究中，研究了iNOS和生存素mRNA的表达与癌细胞自发凋亡的发生、增殖活性之间的相关性，以及这些基因的表达在HCC中的预后重要性。
通过手术切除从61例HCC患者和8例非HCC患者的肝脏获取组织。使用逆转录聚合酶链反应（RT-PCR）评估61个肿瘤、61个组织学上相邻的非癌性肝脏和8个正常肝脏中iNOS和生存素mRNA的表达。通过免疫组织化学检测凋亡癌细胞和癌细胞的增殖活性。
61例HCC中有34例（55.7%）检测到iNOS mRNA表达，61例癌旁非癌性肝组织中有19例（31.1%）检测到，8例正常肝脏中均未检测到。此外，61例HCC中有19例（31.1%）检测到生存素mRNA，61例非癌性肝组织中均未检测到，8例正常肝脏中也均未检测到。iNOS mRNA表达与HCC中癌细胞的增殖活性或凋亡发生无关。相反，生存素mRNA表达与癌细胞的高增殖活性和低凋亡指数密切相关。iNOS阳性或阴性HCC患者的疾病特异性生存率无差异。然而，生存素阳性HCC患者的疾病特异性生存率明显低于生存素阴性HCC患者。
这些结果表明，iNOS可能与癌细胞增殖活性或凋亡无关；然而，生存素不仅可能抑制凋亡，还可能加速癌细胞增殖活性，并在HCC的肿瘤进展中起重要作用。
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