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

Abstract

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 highresolution 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 transcriptionpolymerase 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 ¼ 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 (Po0.016). 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. Keywords: hepatocellular carcinoma; deletion hotspots; cDNA array; transcriptional mapping Hepatocellular carcinoma currently ranks the fifth most common malignancy worldwide. 1,2 It carries a high cancer morbidity and mortality because by the time of clinical presentation, more than 80% of patients are at the advance inoperable stage. 2,3 The low efficacy of current screening regime by serum alpha-fetoprotein measurements and transabdominal ultrasound imaging has rendered most patients not being diagnosed in time for curative surgery.Thus, underpinning the genetic events associated with hepatocellular carcinoma is expected to improve our understanding on liver carcinogenesis and also potentially provide biomarkers that are of diagnosis and prognostic values.Molecular studies using loss of heterozygosity analysis and comparative genomic hybridization have revealed recurrent chromosomal changes in hepatocellular carcinoma including losses on 1p, 4q, 6q, 8p, 11q, 13q, 16q and 17p. [4][5][6] As diminutions on 4q, 8p, 16q and 17p have been described in the nontumorous cirrhotic nodules and early preneoplastic liver dysplasia, these changes have been further implicated in the early carcinogenetic events of hepat...

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

“…Other proteins that have also been shown to be elevated in hepatocellular carcinoma include fibrinogen gamma chain precursor [30], glutathione S transferase [31], glycerol-3-phosphate dehydrogenase [32], histone-binding protein RBBP4 [33] and nucleophosmin [34]. Lamin-A/C was elevated in sera of patients with a hepatocellular carcinoma [35].…”

Re-Expression of Transcription FactorATF5in Hepatocellular Carcinoma Induces G2-M Arrest

“…19 in HCC, where abnormalities on 19q could be identified in as much as f50% of primary tumors (7). Common chr.19q aberrations have also been described in a variety of human malignancies, including oligodendroglioma (10), astrocytoma (11), malignant gliomas (12), neuroblastoma (13), and ovarian carcinoma (14), where adverse prognostic associations have been further suggested in astrocytoma (11) and neuroblastoma (13).…”

“…Our study highlighted a tumor suppressive role for ATF5 in HCC and suggested ID1, an oncogenic transcription factor (15), as one of its transcriptionally regulated target. Eleven HCC cell lines (HKCI-1, HKCI-2, HKCI-3, HKCI-4, HKCI-7, HKCI-8, HKCI-9, HKCI-10, HKCI-C1, HKCI-C2, and HKCI-C3) were established from our laboratory and cultured as described previously (17)(18)(19). Hep3B, PLC/ PRF/5, HepG2, Huh7, SNU387, SNU398, and SNU475 were cultured according to American Type Culture Collection recommendations.…”

CMTM3, Located at the Critical Tumor Suppressor Locus 16q22.1, Is Silenced by CpG Methylation in Carcinomas and Inhibits Tumor Cell Growth through Inducing Apoptosis

“…CMTM3 is linked to CMTM4, with both located closely on 16q22.1, which is frequently deleted in multiple tumors, such as hepatocellular, breast, and prostate tumors and retinoblastoma, suggesting the presence of critical tumor suppressor genes (TSG) at this locus (8)(9)(10)(11).…”