Self‐organizing‐map‐based molecular signature representing the development of hepatocellular carcinoma

Iizuka, Norio; Oka, M.; Yamada-Okabe, Hisafumi; Mori, Naohide; Tamesa, Takao; Okada, Toshimasa; Takemoto, Norikazu; Sakamoto, Kazuhiko; Hamada, Kenji; Ishitsuka, Hideo; Miyamoto, Takanobu; Uchimura, Shunji; Hamamoto, Yoshihiko

doi:10.1016/j.febslet.2004.10.113

Cited by 34 publications

(43 citation statements)

References 40 publications

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“…A number of overexpressed genes encoding for secreted (e.g., GPC3, LCN2 and DKK1) or membrane-bound proteins (e.g., GPC3, IGSF1 and PSK-1), which may be attractive candidates for the diagnosis of HCC, have also been identified (Patil et al, 2005). In the analysis of 102 tumors from 82 HBV and HCV patients, Chen et al did not find any consistent distinction between the two groups, whereas other studies could identify at least some distinctive trends between HBV-and HCV-related HCCs (Iizuka et al, 2002;Delpuech et al, 2002). However, as for the study of viral genes, no specific gene signature has been found that might clearly explain as to how HBV or HCV mediates oncogenesis.…”

Section: Occult Hbv Infectionmentioning

confidence: 73%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type b-catenin and the Wnt-b-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/b-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

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Section: Occult Hbv Infectionmentioning

confidence: 73%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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“…40 Previous microarray studies have showed that several isoforms of metallothionein such as MT1A and MT1F are frequently downregulated in hepatocellular carcinoma compared to nontumorous livers. [41][42][43] However, none of these studies has attempted validation analysis. In this study, our array finding concurred with qRT-PCR verifications, which also indicated the repressions of MT1G corresponded to the highest incidence (63%) and magnitude in hepatocellular carcinoma tumors relative to their adjacent nonmalignant liver tissue (P ¼ 0.0001) ( Table 3).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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...

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“…The most prominent among them being up-regulated-Axl, Cbr3, Cd36, Lgals1, Lgals3, Jun, and Ubd; down-regulated-Ahcy, Cbs, Gnmt (three genes encoding enzymes that control Sadenosylmethionine catabolism), C6, C8a, C8b (encoding complement components), and cytochrome P450 genes Cyp1a2, Cyp2e1, Cyp4v3, Cyp8b1 (8,(25)(26)(27)(28)(29). Overexpression of the Ubd protein may cause chromosomal instability (30).…”

Section: Comparison With Published Datamentioning

confidence: 99%

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Research

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Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-knockout (Mdr2-KO) mice, a model of inflammationassociated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling showed that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC data sets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time reverse transcription-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We show that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in most dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA, level.These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of B-catenin activation.In conclusion, the Mdr2-KO mouse may serve as a model for B-catenin -negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes.

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Self‐organizing‐map‐based molecular signature representing the development of hepatocellular carcinoma

Cited by 34 publications

References 40 publications

Viral hepatitis and liver cancer: the case of hepatitis C

Viral hepatitis and liver cancer: the case of hepatitis C

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

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

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