Kyo Satoru, Takakura Masahiro, Fujiwara Toshiyoshi, Inoue Masaki
Department of Obstetrics and Gynecology, Kanazawa University, Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
Cancer Sci. 2008 Aug;99(8):1528-38. doi: 10.1111/j.1349-7006.2008.00878.x.
Telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres, but the activation mechanism during carcinogenesis remains unclear. Transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is the major mechanism for cancer-specific activation of telomerase, and a number of factors have been identified to directly or indirectly regulate the hTERT promoter, including cellular transcriptional activators (c-Myc, Sp1, HIF-1, AP2, ER, Ets, etc.) as well as the repressors, most of which comprise tumor suppressor gene products, such as p53, WT1, and Menin. Nevertheless, none of them can clearly account for the cancer specificity of hTERT expression. The chromatin structure via the DNA methylation or modulation of nucleosome histones has recently been suggested to be important for regulation of the hTERT promoter. DNA unmethylation or histone methylation around the transcription start site of the hTERT promoter triggers the recruitment of histone acetyltransferase (HAT) activity, allowing hTERT transcription. These facts prompted us to apply these regulatory mechanisms to cancer diagnostics and therapeutics. Telomerase-specific replicative adenovirus (Telomelysin, OBP-301), in which E1A and E1B genes are driven by the hTERT promoter, has been developed as an oncolytic virus that replicates specifically in cancer cells and causes cell death via viral toxicity. Direct administration of Telomelysin was proved to effectively eradicate solid tumors in vivo, without apparent adverse effects. Clinical trials using Telomelysin for cancer patients with progressive stages are currently ongoing. Furthermore, we incorporated green fluorescent protein gene (GFP) into Telomelysin (TelomeScan, OBP-401). Administration of TelomeScan into the primary tumor enabled the visualization of cancer cells under the cooled charged-coupled device (CCD) camera, not only in primary tumors but also the metastatic foci. This technology can be applied to intraoperative imaging of metastatic lymphnodes. Thus, we found novel tools for cancer diagnostics and therapeutics by utilizing the hTERT promoter.
端粒酶激活是通过维持端粒而促进人类致癌作用的关键步骤，但致癌过程中的激活机制仍不清楚。人类端粒酶逆转录酶（hTERT）基因的转录调控是端粒酶癌症特异性激活的主要机制，并且已经鉴定出许多直接或间接调节hTERT启动子的因子，包括细胞转录激活因子（c-Myc、Sp1、HIF-1、AP2、ER、Ets等）以及阻遏物，其中大多数包含肿瘤抑制基因产物，如p53、WT1和Menin。然而，它们都不能清楚地解释hTERT表达的癌症特异性。最近有人提出，通过DNA甲基化或核小体组蛋白的调节形成的染色质结构对于hTERT启动子的调控很重要。hTERT启动子转录起始位点周围的DNA去甲基化或组蛋白甲基化会触发组蛋白乙酰转移酶（HAT）活性的募集，从而允许hTERT转录。这些事实促使我们将这些调控机制应用于癌症诊断和治疗。端粒酶特异性复制性腺病毒（Telomelysin，OBP-301），其中E1A和E1B基因由hTERT启动子驱动，已被开发为一种溶瘤病毒，可在癌细胞中特异性复制并通过病毒毒性导致细胞死亡。事实证明，直接施用Telomelysin可有效根除体内实体瘤，且无明显不良反应。目前正在对进展期癌症患者进行使用Telomelysin的临床试验。此外，我们将绿色荧光蛋白基因（GFP）整合到Telomelysin中（TelomeScan，OBP-401）。将TelomeScan施用于原发性肿瘤能够在冷却电荷耦合器件（CCD）相机下观察到癌细胞，不仅在原发性肿瘤中，而且在转移灶中也能观察到。该技术可应用于转移性淋巴结的术中成像。因此，我们通过利用hTERT启动子找到了用于癌症诊断和治疗的新工具。
