State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Hepatology. 2010 May;51(5):1624-34. doi: 10.1002/hep.23540.
Loss of 16q is one of the most frequent alterations in many malignancies including hepatocellular carcinomas (HCC), suggesting the existence of a tumor suppressor gene (TSG) within the frequently deleted region. In this report we describe the identification and characterization of one candidate TSG, tyrosine aminotransferase gene (TAT), at 16q22.1. Loss of one TAT allele was detected in 27/50 (54%) of primary HCCs by quantitative real-time polymerase chain reaction. In addition, homo-deletion of TAT alleles was detected in two cases. Down-regulation of TAT was detected in 28/50 (56%) of HCCs, which was significantly associated with the loss of TAT allele and hypermethylation of TAT 5' CpG island (CGI) region (P < 0.001). Functional studies found that TAT has a strong tumor suppressive ability. Introduction of the TAT gene into HCC cell lines could effectively inhibit colony formation in soft agar, foci formation, and tumor formation in nude mice. Further study found that the tumor suppressive mechanism of TAT was associated with its proapoptotic role in a mitochondrial-dependent manner by promoting cytochrome-c release and activating caspase-9 and PARP.
Taken together, our findings suggest that TAT plays an important suppressive role in the development and progression of HCC.
16q 的缺失是许多恶性肿瘤（包括肝细胞癌 [HCC]）中最常见的改变之一，这表明在频繁缺失的区域存在肿瘤抑制基因（TSG）。在本报告中，我们描述了在 16q22.1 上鉴定和表征一个候选 TSG，即酪氨酸转氨酶基因（TAT）。通过定量实时聚合酶链反应检测到 50 个原发性 HCC 中有 27 个（54%）存在一个 TAT 等位基因丢失。此外，在两个病例中检测到 TAT 等位基因的纯合缺失。在 50 个 HCC 中有 28 个（56%）检测到 TAT 的下调，这与 TAT 等位基因丢失和 TAT5'CpG 岛（CGI）区域的高甲基化显著相关（P<0.001）。功能研究发现 TAT 具有很强的肿瘤抑制能力。将 TAT 基因导入 HCC 细胞系可有效抑制软琼脂中的集落形成、焦点形成和裸鼠中的肿瘤形成。进一步的研究发现，TAT 的肿瘤抑制机制与其在线粒体依赖性的促细胞色素 c 释放和激活 caspase-9 和 PARP 的促凋亡作用有关。
综上所述，我们的研究结果表明 TAT 在 HCC 的发生和发展中发挥重要的抑制作用。
