Tumor suppressor and hepatocellular carcinoma

Martin, Juliette; Dufour, Jean‐François

doi:10.3748/wjg.14.1720

Cited by 73 publications

(54 citation statements)

References 178 publications

(258 reference statements)

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“…It has been shown that the activity of more than 20 different TSGs is lost in HCC due to mutations or due to hyper-methylation of their promoters. 24 The TSGs include micro-RNAs which behave as tumor suppressors.…”

Section: Liver Specific Tumor Suppressor Genesmentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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Liver cancer is one of the most lethal cancers. Quiescent liver expresses up to 20 tumor suppressor proteins including Rb, p53, CCAAT-Enhancer-Binding Protein (C/EBP)α, Hepatocyte Nuclear Factor (HNF4)α and p16 and it is well protected from development of liver cancer. However, the negative control of liver proliferation by these factors and other tumor suppressor genes is eliminated in liver cancer. Studies of liver regeneration after surgery and injury have provided fundamental mechanisms on how liver neutralizes tumor suppressor proteins for the time of regeneration; however, studies of liver cancer in animal models and in human samples showed several additional pathways of this neutralization. One of these additional pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is dramatically increased in human hepatocellular carcinoma (HCC) and in animal models of carcinogenesis. Once activated Gankyrin triggers degradation of main tumor suppressor proteins during development of liver cancer using slightly different mechanisms. Recent studies identified mechanisms which repress Gankyrin in quiescent livers and mechanisms of activation of Gankyrin in liver cancer. These mechanisms involve a communication between Farnesoid X Receptor (FXR) signaling and chromatin remodelling proteins mediated by members of C/EBP family. It has been recently shown that C/EBPα plays a critical role in this network and that the activation of C/EBPα in cirrhotic livers with HCC inhibits cancer progression. This C/EBPα-dependent inhibition of liver cancer involves activation of a majority of tumor suppressor genes and repression of tumor initiating pathways such as β-catenin and c-myc. These recent findings provide a background for FXR-based and C/EBPα-based approaches to treat liver cancer.

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Section: Liver Specific Tumor Suppressor Genesmentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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“…TGF-ß signaling has been implicated in cancer progression among many different types of cancer including hepatocarcinogenesis (22). Several studies have demonstrated that TGF-ß is overexpressed in HCC (23,24).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of transforming growth factor β receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity

Nam¹

2009

Oncol Rep

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Abstract. The transforming growth factor receptor III (TGFßRIII) is the most abundant and essential TGF-ß binding protein that functions as a co-receptor with other receptors in TGF-ß signaling. In earlier studies, expression of TGFßRIII was reported to be decreased in a variety of human cancers. Functional assessment of TGFßRIII was performed in many previously studied cancers but not in hepatocellular carcinoma. Therefore, in this study, we investigated the expression and genetic alterations of TGFßRIII in hepatocellular carcinoma (HCC) by quantitative real-time PCR (qRT-PCR) and singlestrand conformation polymorphism (SSCP) analysis. The qRT-PCR showed down-regulation of TGFßRIII in the tumor samples. To investigate whether genetic alterations mediated decreased expression of TGFßRIII, we performed mutation analysis of 67 human HCC tissues by SSCP and direct sequencing. We found five previously reported and one novel single nucleotide polymorphisms in exons 2, 3, 5, 13 and 14, but no mutations were detected. These polymorphisms were not associated with amino acid changes except for a base change found in exon 2 (TCC→TTC, S15F). The loss of heterozygosity (LOH) analysis performed on 10 tumors and corresponding normal pairs, showed a low rate of LOH (2/10). The results of this study suggest that TGFßRIII is transcriptionally down-regulated in hepatocellular carcinoma. In addition, genetic alterations did not appear to be associated with the reduced expression level of TGFßRIII. To clarify the role of TGFßRIII in hepatocellular tumor development and progression, functional analysis is needed in future studies.

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“…Liver cancer remains the fifth most common cancer and the third most common cause of cancerrelated death in the world (2). The mechanisms of cancer-related elimination or reduction of tumor suppressor proteins include transcriptional repression of the genes, degradation of proteins, and posttranslational modifications that change biological activities of these proteins (1,3,4). A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

Lewis

Valanejad

Cast

et al. 2017

Molecular and Cellular Biology

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Despite intensive investigations, mechanisms of liver cancer are not known. Here, we identified an important step of liver cancer, which is the neutralization of tumor suppressor activities of an RNA binding protein, CUGBP1. The translational activity of CUGBP1 is activated by dephosphorylation at Ser302. We generated CUGBP1-S302A knock-in mice and found that the reduction of translational activity of CUGBP1 causes development of a fatty liver phenotype in young S302A mice. Examination of liver cancer in diethylnitrosamine (DEN)-treated CUGBP1-S302A mice showed these mice develop much more severe liver cancer that is associated with elimination of the mutant CUGBP1. Searching for mechanisms of this elimination, we found that the oncoprotein gankyrin (Gank) preferentially binds to and triggers degradation of dephosphorylated CUGBP1 (de-ph-S302-CUGBP1) or S302A mutant CUGBP1. To test the role of Gank in degradation of CUGBP1, we generated mice with liver-specific deletion of Gank. In these mice, the tumor suppressor isoform of CUGBP1 is protected from Gank-mediated degradation. Consistent with reduction of CUGBP1 in animal models, CUGBP1 is reduced in patients with pediatric liver cancer. Thus, this work presents evidence that de-ph-S302-CUGBP1 is a tumor suppressor protein and that the Gank-UPS-mediated reduction of CUGBP1 is a key event in the development of liver cancer. KEYWORDS CUGBP1, HCC, HBL, gankyrin, C/EBP␤, phosphorylation, C/EBP Q uiescent livers express up to 20 tumor suppressor proteins (1); however, they are eliminated by different mechanisms under conditions of liver cancer. Liver cancer remains the fifth most common cancer and the third most common cause of cancerrelated death in the world (2). The mechanisms of cancer-related elimination or reduction of tumor suppressor proteins include transcriptional repression of the genes, degradation of proteins, and posttranslational modifications that change biological activities of these proteins (1, 3, 4). A number of recent papers showed that certain proteins work as oncoproteins and as tumor suppressors depending on cell environment, target genes, and posttranslational modifications (5-12). In this regard, Dreijerink et al. have recently shown that menin tumor suppressor protein displays its tumor suppression activity in a variety of cancer cells; however, it possesses oncogenic activities in breast tumorigenesis (5). Another recent report revealed that the Kruppelassociated box zinc finger protein ZNF224 can behave as an oncoprotein and as a tumor suppressor protein and that these opposite activities of ZNF224 are controlled by specific protein-protein interactions (6). In addition to the opposite changes of the activities of tumor suppressor proteins and oncogenes, certain microRNAs display cell type-specific oncogenic or tumor suppression activities. Hickey et al. recently demon-

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Tumor suppressor and hepatocellular carcinoma

Cited by 73 publications

References 178 publications

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Down-regulation of transforming growth factor β receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity

RNA Binding Protein CUGBP1 Inhibits Liver Cancer in a Phosphorylation-Dependent Manner

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