Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma

Umemura, Atsushi; Itoh, Yoshito; Itoh, Katsuhiko; Yamaguchi, Kanji; Nakajima, Tomoki; Higashitsuji, Hiroaki; Onoue, Hitoshi; Fukumoto, Manabu; Okanoue, Takeshi; Fujita, Jun

doi:10.1002/hep.22027

Cited by 51 publications

(41 citation statements)

References 32 publications

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“…Most authors have reported that the prevalent type of HCC is of a moderately differentiated to well-differentiated grade with β-catenin expression at the membrane and in the cytoplasm [14,29,30]. These conclusions are consistent with recent results showing that p28 GANK plays an oncogenic role primarily at the early stages of human hepatocarcinogenesis [36]. β-catenin can enter the nucleus and regulate the transcription of target genes such as cyclin D1 and c-Myc [10,30].…”

Section: Discussionsupporting

confidence: 81%

The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling

et al. 2011

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p28GANK (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28GANK mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28 GANK is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28 GANK expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28 GANK expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28 GANK -mediated activation of β-catenin. p28 GANK overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28 GANK resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28 GANK , and a correlation between p28 GANK overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28 GANK expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.

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Section: Discussionsupporting

confidence: 81%

The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling

et al. 2011

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“…22 When gankyrin was silenced in hepatocellular carcinoma cell lines with wt and mutated P53, a different phenotype was induced in the wt P53 cells, with up-regulation of p53 levels and subsequent activation of caspase 9 and induction of apoptosis. 33 Our results showed stronger inhibition of cell growth and a greater pro-apoptotic effect after miR-214 transfection in cell lines with wt and functional P53 than in mutated P53 cell lines. However, apoptosis was also induced in JJN3 cells, which although they do not carry the P53 mutation, do have impaired activity of the p53 pathway.…”

Section: Discussionsupporting

confidence: 50%

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

et al. 2012

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“…34), and liver cancer (IGFBP5; ref. 35). Many cancer-related genesets and several oncogenic signatures were enriched in genes upregulated in transformed Smchd1-null MEFs and/or tumors, including E2F3 (29 genes, P < 0.05), E2F1/E2F (2 genesets, P < 0.05), and BRCA1/2 pathways (5 genesets, P < 0.01), which may explain the accelerated tumor growth in the absence of Smchd1.…”

Section: Smchd1 Deficiency Leads To Increased Clonogenicity Of Premalmentioning

confidence: 97%

Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor

Leong

Chen

et al. 2013

Cancer Research

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SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Em-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Em-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers. Cancer Res; 73(5);

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Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma

Cited by 51 publications

References 32 publications

The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling

The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor

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