TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas.
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 squamous 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.
Yasui
Kohichiroh
K
Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Japan.
Arii
Shigeki
S
Zhao
Chen
C
Imoto
Issei
I
Ueda
Masakazu
M
Nagai
Hisaki
H
Emi
Mitsuru
M
Inazawa
Johji
J
D064194:Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002882:Chromosomes, Human, Pair 13; D044842:Cullin Proteins; D019927:Cyclin E / Q000235:genetics; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D064194:Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome; D014408:Biomarkers, Tumor; C577395:CDC16 protein, human; C114234:CUL4A protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D019927:Cyclin E; D005819:Genetic Markers; D009363:Neoplasm Proteins; C493735:TFDP1 protein, human; D050680:Transcription Factor DP1; D014157:Transcription Factors