Chan Kathy Y-Y, Lai Paul B-S, Squire Jeremy A, Beheshti Ben, Wong Navy L-Y, Sy Shirley M-H, Wong Nathalie
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, NT, SAR Hong Kong, China.
Mod Pathol. 2006 Dec;19(12):1546-54. doi: 10.1038/modpathol.3800674. Epub 2006 Sep 15.
Molecular characterizations of hepatocellular carcinoma have indicated frequent allelic losses on chromosomes 4q, 8p, 16q and 17p, where the minimal deleted regions have been further defined on 4q12-q23, 4q31-q35, 8p21-p22, 16q12.1-q23.1 and 17p13. Despite these regions are now well-recognized in early liver carcinogenesis, few underlying candidate genes have been identified. In an effort to define affected genes within common deleted loci of hepatocellular carcinoma, we conducted transcriptional mapping by high-resolution cDNA microarray analysis. In 20 hepatocellular carcinoma cell lines and 20 primary tumors studied, consistent downregulations of novel transcripts were highlighted throughout the entire genome and within sites of frequent losses. The array-derived candidates including fibrinogen gamma peptide (FGG, at 4q31.3), vitamin D binding protein (at 4q13.3), fibrinogen-like 1 (FGL1, at 8p22), metallothionein 1G (MT1G, at 16q12.2) and alpha-2-plasmin inhibitor (SERPINF2, at 17p13) were confirmed by quantitative reverse transcription-polymerase chain reaction, which also indicated a more profound downregulation of FGL1, MT1G and SERPINF2 relative to reported tumor-suppressor genes, such as DLC1 (8p22), E-cadherin (16q22.1) and TP53 (17p13.1). In primary hepatocellular carcinoma examined, a significant repression of MT1G by more than 100-fold was indicated in 63% of tumors compared to the adjacent nonmalignant liver (P = 0.0001). Significant downregulations of FGG, FGL1 and SERPINF2 were also suggested in 30, 23 and 33% of cases, respectively, compared to their nonmalignant counterparts (P < 0.016). In summary, transcriptional mapping by microarray indicated a number of previously undescribed downregulated genes in hepatocellular carcinoma, and highlighted potential candidates within common deleted regions.
肝细胞癌的分子特征表明，在染色体4q、8p、16q和17p上频繁出现等位基因缺失，其中最小缺失区域已进一步确定为4q12 - q23、4q31 - q35、8p21 - p22、16q12.1 - q23.1和17p13。尽管这些区域在早期肝癌发生过程中已得到充分认识，但尚未确定潜在的候选基因。为了确定肝细胞癌常见缺失位点内的受影响基因，我们通过高分辨率cDNA微阵列分析进行转录图谱绘制。在研究的20个肝癌细胞系和20个原发性肿瘤中，整个基因组以及频繁缺失位点内均突出显示了新转录本的一致下调。通过定量逆转录 - 聚合酶链反应证实了阵列衍生的候选基因，包括纤维蛋白原γ肽（FGG，位于4q31.3）、维生素D结合蛋白（位于4q13.3）、纤维蛋白原样1（FGL1，位于8p22）、金属硫蛋白1G（MT1G，位于16q12.2）和α - 2 - 纤溶酶抑制剂（SERPINF2，位于17p13），这也表明相对于报道的肿瘤抑制基因，如DLC1（8p22）、E - 钙黏蛋白（16q22.1）和TP53（17p13.1），FGL1、MT1G和SERPINF2的下调更为显著。在检测的原发性肝细胞癌中，与相邻的非恶性肝脏相比，63%的肿瘤中MT1G的表达显著抑制超过100倍（P = 0.0001）。与非恶性对应物相比，分别在30%、23%和33%的病例中也提示FGG、FGL1和SERPINF2有显著下调（P < 0.016）。总之，通过微阵列进行转录图谱绘制表明，肝癌中有许多先前未描述的下调基因，并突出了常见缺失区域内的潜在候选基因。
