Research IndicatorsGraph generated 29 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: PSMD10 (cancer-related)
The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.
Ren YB, Luo T, Li J, et al.p28(GANK) associates with p300 to attenuate the acetylation of RelA.
Mol Carcinog. 2015; 54(12):1626-35 [PubMed
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Oncoprotein p28(GANK), overexpressed in hepatocellular carcinomas (HCC), binds to RelA and retains NF-κB in the cytoplasm to suppress NF-κB transactivation. However, the mechanism has not yet been elucidated. In this study, we clarified the mechanism of NF-κB regulated by p28(GANK). p28(GANK) reduced TNF-α-induced nuclear translocation of RelA/NF-κB independent of HDAC3. p28(GANK) interacted with p300 to attenuate assembly of RelA with p300, which lessened acetylation of RelA on the lysine 310 sites. Moreover, overexpression of p28(GANK) attenuated the capability of NF-κB binding to the target gene IκBα promoter, but also weakened adriamycin-induced NF-κB pro-apoptotic gene Fas and FasL expression, which subsequently made p53-deficient tumor cells resistance to adriamycin. These results present mechanistic insight into the key role of p28(GANK) in post-translational regulation of RelA/NF-κB.
Qian YW, Chen Y, Yang W, et al.p28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis.
Gastroenterology. 2012; 142(7):1547-58.e14 [PubMed
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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), although little is known about their stem cell-like properties.
METHODS: We quantified levels of p28(GANK) (Gankyrin), OV6, and Oct4 in 130 human HCC samples using immunohistochemistry. Magnetic-activated cell sorting was used to isolate OV6+ HCC cells. T-IC properties were evaluated by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and spheroid formation. We used a coimmunoprecipitation assay to study interactions among p28(GANK), Oct4, and WWP2. Tumorigenicity and pulmonary metastasis were examined in nonobese diabetic and severe combined immunodeficient mice.
RESULTS: In HCC samples, high levels of p28(GANK) correlated with expansion of OV6+ tumor cells; the combination of high levels of p28(GANK) and OV6 was associated with progression of HCC. p28(GANK) was predominantly expressed in liver T-ICs, isolated by magnetic sorting, and undifferentiated primary HCC spheroids. Increased levels of p28(GANK) in T-ICs increased their percentages in HCC samples, expression of stem cell genes, self-renewal potential, chemoresistance in vitro, and tumorigenicity and ability to develop into pulmonary metastases in mice. Conversely, knockdown of p28(GANK) reduced their T-IC properties. p28(GANK) likely activates liver T-ICs by impeding ubiquitination and degradation of the transcription factor Oct4 by WWP2. In support of this concept, levels of p28(GANK) correlated with those of Oct4 in HCC samples.
CONCLUSIONS: p28(GANK) activates and maintains liver T-ICs in HCCs by preventing degradation of Oct4. Inhibitors of p28(GANK) might therefore be developed to inactivate T-ICs and slow tumor progression.
p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) 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.
Dai RY, Chen Y, Fu J, et al.p28GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity.
Cell Res. 2009; 19(11):1243-57 [PubMed
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It has been shown that oncoprotein p28(GANK), which is consistently overexpressed in human hepatocellular carcinoma (HCC), plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28(GANK) inhibits apoptosis in HCC cells induced by the endoplasmic reticulum (ER) stress. During ER stress, p28(GANK) enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell's ability to cope with the stress conditions. Furthermore, p28(GANK) upregulates glucose-regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28(GANK) increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B (NF-kappaB) activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28(GANK) inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28(GANK) has potential implications for HCC progression under the ER stress conditions.
Tan L, Fu XY, Liu SQ, et al.Expression of p28GANK and its correlation with RB in human hepatocellular carcinoma.
Liver Int. 2005; 25(3):667-76 [PubMed
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BACKGROUND: Aberrance of retinoblastoma protein (RB) signal pathway is known to play an important role in the carcinogenesis of human hepatocellular carcinoma (HCC). p28GANK, originally purified from human 26S proteasome as a non-ATPase subunit, was recently found in HCC and shown to interact with RB. The aim of this study was to investigate the expression profile of p28GANK and its correlation with RB in HCC.
METHODS: The expression of p28GANK was evaluated in 55 surgically resected HCCs by immunohistochemistry (IHC), and the associations were explored between p28GANK level and clinicopathologic features as well as tumor suppressor RB. Western blotting was performed to determine p28GANK expression level in 12 HCCs. Immunofluorescence stainings of p28GANK and RB in U2-OS cells were examined by confocal microscopy.
RESULTS: Positive p28GANK cytoplasmic staining was recognized in 55 HCCs. Nuclear positive occurrence of p28(GANK) in HCCs was more frequent than paracancerous hepatic tissues (P < 0.05). The overexpression probability of p28GANK was inversely associated with Edmonson's grade: overexpression occurred in nine out of 11 (81.8%), 22 out of 35 (62.9%) and two out of nine (22.2%) in I-II, III and IV graded cases, respectively (P = 0.004). Total cellular expression of p28GANK had curvilinear correlation with the nuclear expression of RB (r = 0.475, P = 0.019), while the nuclear expression of p28GANK had not. Western blot analysis showed that up-regulation of p28GANK expression was found in nine out of 12 HCCs compared with paracancerous liver tissues. Exogenously expressed p28GANK colocalized with RB in cytoplasm of U2-OS cells.
CONCLUSIONS: These results confirm the role of p28GANK as a highly expressed oncoprotein in HCC by in situ examination. Its overexpression correlates with the differentiation status of HCC. The whole cellular p28GANK activation, not nuclear portion only, influences the alteration of RB. Underlying nuclear translocation of p28GANK may contribute to the counteraction against RB through a feed back loop. These data provide new evidence for p28GANK to be used as a promising drug target of a therapeutic agent against HCC.
Fu X, Tan L, Liu S, et al.A novel diagnostic marker, p28GANK distinguishes hepatocellular carcinoma from potential mimics.
J Cancer Res Clin Oncol. 2004; 130(9):514-20 [PubMed
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PURPOSE: To investigate the sensitivity, specificity, and spatial distribution of the product of p28 gene (p28(GANK) protein) in human hepatocellular carcinoma (HCC) and nonhepatocellular carcinomas in relation to immunostaining with Cytokeratin 18 (CK18), alpha-fetoprotein (AFP), and Hepatocyte paraffin 1 (HepPar1).
METHOD: In this retrospective study, formalin-fixed paraffin-embedded tissues from 24 HCCs, five intrahepatic cholangiocarcinomas (ICC), five combined hepatocellular cholangiocarcinomas (C-HCC-CC) and mine metastatic hepatic carcinomas (MHC) were immunostained for p28(GANK) as well as CK18, AFP and HepPar1. Only cases with more intensified staining in carcinoma contrast to the adjacent liver tissues were accepted as positive.
RESULT: In HCC, p28(GANK) was expressed restrictively in hepatocytes of both para-lesion and carcinoma liver tissues, while absent in the bile duct epithelial cells, Kupffer cells, and other interstitial cells. The positive staining of p28(GANK) was noted in 16 (66.7%) specimens of HCC and three (60.0%) specimens of C-HCC-CC, and no specific lesion staining was found in all tested specimens of ICC and MHC. Sensitivity and specificity for hepatocyte-originated carcinoma were, respectively, 65.5% and 100% for p28(GANK), 79.3% and 85.2% for CK18, 20.7% and 100% for AFP, 79.3% and 92.0% for HepPar1.
CONCLUSION: The hepatocytic staining for p28(GANK) is clearly useful in differentiating hepatocyte-originated carcinoma from non-HCC. p28(GANK) may be used as an ancillary marker for the diagnosis of HCC.