Terasaki Tadashi, Kyo Satoru, Takakura Masahiro, Maida Yoshiko, Tsuchiya Hiroyuki, Tomita Katsuro, Inoue Masaki
Department of Orthopedic Surgery, Kanazawa University, School of Medicine, Kanazawa, Ishikawa 920-8641, Japan.
Oncol Rep. 2004 Jun;11(6):1307-11.
Telomerase activation is prevalent in most epithelial tumors, and may be a critical step in cellular immortalization and carcinogenesis. However, telomerase activity in tumors of mesenchymal origin is not well understood. In the present study, we examined telomerase activity in clinical samples from osteosarcoma and soft tissue sarcoma and representative sarcoma cell lines (HOS, OST and Saos2), using the telomeric repeat amplification protocol (TRAP) assay. The cell lines HOS and OST were telomerase-positive, but Saos2 cells lacked telomerase activity and hTERT mRNA expression. Treatment of Saos2 cells with the demethylating agent 5-aza-2'-deoxy-cytidine, alone or together with the histone deacetylase inhibitor tricostatin A, did not induce hTERT mRNA expression. Twenty-six of the 83 sarcoma samples (31.3%) were telomerase-positive [bone sarcoma, 15 of 42 samples (35.7%); soft tissue sarcoma, 11 of 41 samples (26.8%)], whereas neither benign tumors nor normal bone tissue expressed telomerase activity. There was no significant correlation between histological type, tumor staging and telomerase activity. However, patients with telomerase-positive tumors had significantly shorter survival than those with telomerase-negative tumors. There was heterogeneity in telomere length (range, 6-18 kb) among the tumors examined, but there was no significant difference in length between telomerase-positive and -negative tumors. Thus, these mesenchymal tumors comprise heterologous groups, some positive and some negative for telomerase, with long and short telomeres, suggesting multiple carcinogenesis pathways. The present results indicate that telomerase activation is not prevalent in mesenchymal tumors and is not a critical determinant of telomere length, but it may be a prognostic indicator of mesenchymal tumors.
端粒酶激活在大多数上皮性肿瘤中普遍存在，可能是细胞永生化和致癌过程中的关键步骤。然而，间充质起源肿瘤中的端粒酶活性尚未得到充分了解。在本研究中，我们使用端粒重复序列扩增法（TRAP）检测了骨肉瘤和软组织肉瘤临床样本以及代表性肉瘤细胞系（HOS、OST和Saos2）中的端粒酶活性。细胞系HOS和OST端粒酶呈阳性，但Saos2细胞缺乏端粒酶活性和hTERT mRNA表达。用去甲基化剂5-氮杂-2'-脱氧胞苷单独或与组蛋白脱乙酰酶抑制剂曲古抑菌素A联合处理Saos2细胞，均未诱导hTERT mRNA表达。83个肉瘤样本中有26个（31.3%）端粒酶呈阳性[骨肉瘤，42个样本中有15个（35.7%）；软组织肉瘤，41个样本中有11个（26.8%）]，而良性肿瘤和正常骨组织均未表达端粒酶活性。组织学类型、肿瘤分期与端粒酶活性之间无显著相关性。然而，端粒酶阳性肿瘤患者的生存期明显短于端粒酶阴性肿瘤患者。在所检测的肿瘤中端粒长度存在异质性（范围为6-18 kb），但端粒酶阳性和阴性肿瘤之间的长度无显著差异。因此，这些间充质肿瘤由异质性群体组成，一些端粒酶阳性，一些端粒酶阴性，端粒有长有短，提示存在多种致癌途径。目前的结果表明，端粒酶激活在间充质肿瘤中并不普遍，也不是端粒长度的关键决定因素，但它可能是间充质肿瘤的一个预后指标。
