TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas

Abstract

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.

Involvement of CUL4 Ubiquitin E3 Ligases in Regulating CDK Inhibitors Dacapo/p27Kip1 and Cyclin E Degradation

“…Since the gene encoding CUL4A is amplified in many breast cancers and hepatocellular carcinomas 46,47 and since low or absent expression of p27 is often associated with malignant cancers, 48 our studies also highlight how altered regulation of CUL4 E3 ligase may contribute to the genesis and progression of human cancers. Inactivation of CUL4A and DDB1 stabilizes p27 protein.…”

The Emerging Role of the COP9 Signalosome in Cancer

“…Importantly, several of these Cullin-based E3s (Cul-E3) have major significance in multiple aspects of cancer initiation and progression that include DNA replication fidelity, cell cycle control, apoptosis, immune response, adhesion, motility, and angiogenesis (3). Other factors, such as gene amplification of Cul4A in 16% of primary breast cancers and potentially in several other tumors and evidence that 47% of primary breast cancers overexpress Cul4A, are indications of Cullin significance in oncogenesis (4,5).…”

Positional expression profiling indicates candidate genes in deletion hotspots of hepatocellular carcinoma

“…9 Candidate genes in the smallest overlapping regions 4q12-q23 10 and 4q31-q35, on the other hands, remains undescribed. 11,12 As regions of aberrant genomic loci can harbor more than one tumor-related genes, such as RASSF1A, MLH1, TGFBR2 and BLU on chromosome 3p21, [13][14][15][16] the existence of more than one tumor-suppressor gene within common deleted sites of hepatocellular carcinoma cannot be ruled out.…”