TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas
TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas
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DOI：
10.1053/jhep.2002.33683
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发表时间：
2002-06-01
期刊：
影响因子：
13.5
通讯作者：
Inazawa, J
中科院分区：
文献类型：
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作者：
Yasui, K;Arii, S;Inazawa, J
我们对11个肝细胞癌细胞系和51个原发性肝细胞癌细胞系进行了分子细胞遗传学表征。比较基因组杂交（CGH）显示13q34位点频繁扩增，我们在其他几种类型的肿瘤中检测到扩增，包括食管癌。鳞状细胞癌（ESC）先前，我们认为编码转录因子DP-1的TFDP1可能参与了在原发性ESC中观察到的13q34扩增。因此，我们研究了包括TFDP1在内的5个基因在扩增区域的扩增和表达水平，以探索hcc中13q34位点的扩增靶点。其中3个基因TFDP1、CUL4A （cullin 4A）和CDC16（细胞分裂周期16）在某些细胞系中表现出明显的扩增和过表达。此外，它们在51例原发性hcc中的3或4例中被扩增，并且在2例肿瘤中均被扩增，其表达模式与扩增模式相关。为了阐明TFDP1在HCC中的功能作用，我们采用实时定量PCR检测了TFDP1下游基因的表达水平。细胞周期蛋白E基因（CCNE1）的表达与TFDP1的表达密切相关，不仅在细胞系中，在原发肿瘤中也是如此。以TFDP1为靶点的反义寡核苷酸处理HCC细胞，导致CCNE1下调，提示TFDP1过表达导致CCNE1上调，而CCNE1编码细胞周期G1/S转变的正调节因子。总之，我们的研究结果表明，TFDP1、CUL4A和CDC16可能是一种扩增机制的靶点，因此可能共同或单独参与某些hcc的发生和/或进展。
We carried out molecular cytogenetic characterization of 11 cell lines derived from hepatocellular carcinomas (HCCs) and 51 primary HCCs. Comparative genomic hybridization (CGH) revealed frequent amplification at 13q34, where we had detected amplification in several other types of tumor, including esophageal. squamons cell carcinomas (ESC). Previously, we suggested possible involvement of TFDP1, encoding a transcription factor DP-1, in the 13q34 amplification observed in a primary ESC. Therefore, we investigated amplifications and expression levels of 5 genes mapped on the amplified region, including TFDP1, for exploring amplification targets at 13q34 in HCCs. 3 of those genes, TFDP1, CUL4A (cullin 4A), and CDC16 (cell division cycle 16), showed distinct amplification and consequent over-expression in some cell lines. Moreover, each was amplified in 3 or 4 of the 51 primary HCCs, and all 3 were amplified in 2 tumors, in which their expression patterns correlated with amplification patterns. To elucidate the functional role of TFDP1 in HCC, we examined expression levels of genes downstream of TFDP1 with real-time quantitative polymerase chain reaction (PCR). Expression of cyclin E gene (CCNE1) correlated closely with that of TFDP1 in not only cell lines, but also primary tumors. Treatment of HCC cells with the antisense oligonucleotide targeting TFDP1 resulted in down-regulation of CCNE1, suggesting that TFDP1 overexpression led to up-regulation of CCNE1 that encoded a positive regulator for cell cycle G1/S transition. In conclusion, our findings suggest that TFDP1, CUL4A, and CDC16 are probable targets of an amplification mechanism and therefore may be involved, together or separately, in development and/or progression of some HCCs.