PSMB8 and PBK as potential gastric cancer subtype-specific biomarkers associated with prognosis

Kwon, Chae Hwa; Park, Hye Ji; Choi, Yongju; Kim, Ahrong; Kim, Hye Won; Choi, Jin Hwa; Hwang, Chungsu; Lee, So Jung; Choi, Chang In; Jeon, Tae Yong; Kim, Dae Hwan; Kim, Gwang Ha; Park, Do Youn

doi:10.18632/oncotarget.7411

Cited by 61 publications

(56 citation statements)

References 42 publications

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“…45 PSMB8 expression was first reported as a predictive prognostic factor in gastric cancer. 46 We performed immunohistochemical staining of the samples of benign mucinous adenoma, MuOC, SeOC, COREAD and STAD. All cases of SeOC showed negative PSMB8 expression.…”

Section: Discussionmentioning

confidence: 99%

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Liew

Huang

Weng

et al. 2018

Intl Journal of Cancer

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Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type‐specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis‐coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second‐generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous‐type‐specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.

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Section: Discussionmentioning

confidence: 99%

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Liew

Huang

Weng

et al. 2018

Intl Journal of Cancer

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“…Also, PBK/TOPK promotes cell migration by modulating PI3K/PTEN/AKT-dependent signalling (Shih et al , 2012). Although more recently, the prognostic significance and some functional analyses of PBK/TOPK in GC were reported (Kwon et al , 2016), to date, there has been no report on the prognostic significance of PBK/TOPK as an independent prognostic factor and its molecular mechanisms through the p53 and PI3K/AKT pathways that contributes to the tumour development of GC. Therefore, we closely wished to investigate the effects of PBK/TOPK overexpression and activation in GC.…”

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confidence: 99%

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma

et al. 2016

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Background:PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine–threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC).Methods:We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003.Results:Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71–14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner.Conclusions:These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.

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“…Different proteasome subunit genes have been found to be associated with several diseases including inflammatory responses. In particular, the role of PSMB8 [27] in gastric cancer has been extensively reported in literature. Also, PSMB9 and PSMB8 have been found to be associated with several gastrointestinal disorders like celiac disease and inflammatory bowel disease.…”

Section: Association Analysis In Uk Biobankmentioning

confidence: 99%

A powerful subset-based gene-set analysis method identifies novel associations and improves interpretation in UK Biobank

Dutta

VandeHaar

Fritsche

et al. 2019

Preprint

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A test of association between the phenotype and a set of genes within a biological pathway can be complementary to single variant or single gene association analysis and provide further insights into the genetic architecture of complex phenotypes. Although multiple methods exist to perform such a gene-set analysis, most have low statistical power when only a small fraction of the genes are associated with the phenotype. Further, since existing methods cannot identify possible genes driving association signals, interpreting results of such association in terms of the underlying genetic mechanism is challenging. Here, we introduce Gene-set analysis Association Using Sparse Signals (GAUSS), a method for gene-set association analysis with GWAS summary statistics. In addition to providing a p-value for association, GAUSS identifies the subset of genes that have the maximal evidence of association and appears to drive the association. Using pre-computed correlation structure among test statistics from a reference panel, the p-value calculation is substantially faster compared to other permutation or simulationbased approaches. Our numerical experiments show that GAUSS can increase power over several existing methods while controlling type-I error under a variety of association models.Through the analysis of summary statistics from the UK Biobank data for 1,403 phenotypes, we show that GAUSS is scalable and can identify associations across many phenotypes and genesets.

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PSMB8 and PBK as potential gastric cancer subtype-specific biomarkers associated with prognosis

Cited by 61 publications

References 42 publications

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma

A powerful subset-based gene-set analysis method identifies novel associations and improves interpretation in UK Biobank

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