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Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling.

ABSTRACT: Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation conferred malignant characteristics including proliferation, invasion, migration and angiogenesis in vitro, and increased tumor growth in vivo via the mitogen-activated protein kinase (MAPK) signaling pathway. Pathway analysis suggested genetic and pharmacologic inhibition of P4HB suppressed MAPK expression and its downstream targets were involved in angiogenesis and invasion. This is the first study that demonstrates the oncogenic roles of P4HB and its underlying mechanism in glioma. Since tumor invasion and Vascularisation are typical hallmarks in malignant glioma, our findings uncover a promising anti-glioma mechanism through P4HB-mediated retardation of MAPK signal transduction.

SUBMITTER: Sun S

PROVIDER: S-EPMC5641099 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling.

Sun Stella S Kiang Karrie M Y KMY Ho Amy S W ASW Lee Derek D Poon Ming-Wai MW Xu Fei-Fan FF Pu Jenny K S JKS Kan Amanda N C ANC Lee Nikki P Y NPY Liu Xiao-Bing XB Man Kwan K Day Philip J R PJR Lui Wai-Man WM Fung Ching-Fai CF Leung Gilberto K K GKK

Oncotarget 20170519 42

Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation ...[more]

PMID: 29069756

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Project description:BackgroundProlyl 4-hydroxylase subunit beta (P4HB) has been reported as a suppressor in ferroptosis. However, no known empirical research has focused on exploring relationships between P4HB and prostate cancer (PCa). In this research, we initially examine the function of P4HB in PCa by thorough analysis of numerous databases and proliferation experiment.MethodsWe analyzed the correlations of P4HB expression with prognosis, clinical features, mutation genes, tumor heterogeneity, stemness, tumor immune microenvironment and PCa cells using multiple databases and in vitro experiment with R 3.6.3 software and its suitable packages.ResultsP4HB was significantly upregulated in tumor tissues compared to normal tissues and was closely related to biochemical recurrence-free survival. In terms of clinical correlations, we found that higher P4HB expression was significantly related to older age, higher Gleason score, advanced T stage and residual tumor. Surprisingly, P4HB had highly diagnostic accuracy of radiotherapy resistance (AUC 0.938). TGF beta signaling pathway and dorso ventral axis formation were upregulated in the group of low-expression P4HB. For tumor stemness, P4HB expression was positively related to EREG.EXPss and RNAss, but was negatively associated with ENHss and DNAss with statistical significance. For tumor heterogeneity, P4HB expression was positively related to MATH, but was negatively associated with tumor ploidy and microsatellite instability. For the overall assessment of TME, we observed that P4HB expression was negatively associated with all parameters, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, stromal score, immune score and ESTIMATE score. Spearman analysis showed that P4HB expression was negatively related to TIDE score with statistical significance. In vitro experiment, RT-qPCR and western blot showed that three siRNAs of P4HB were effective on the knockdown of P4HB expression. Furthermore, we observed that the downregulation of P4HB had significant influence on the cell proliferation of six PCa cell lines, including LNCap, C4-2, C4-2B, PC3, DU145 and 22RV1 cells.ConclusionsIn this study, we found that P4HB might serve as a prognostic biomarker and predict radiotherapy resistance for PCa patients. Downregulation of P4HB expression could inhibit the cell proliferation of PCa cells.

Dataset Information

Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling.

Publications

Endoplasmic reticulum chaperone prolyl 4-hydroxylase, beta polypeptide (P4HB) promotes malignant phenotypes in glioma via MAPK signaling.

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