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

Sun, Stella; Kiang, Karrie Mei Yee; Ho, Amy S.W.; Lee, Derek; Poon, Ming-Wai; Xu, Fei; Pu, Jenny Kan-Suen; Kan, Amanda; Lee, Nikki P.Y.; Liu, Xiaobing; Man, Kwan; Day, Philip J.; Lui, WM; Fung, C. F.; Leung, Gilberto Ka-Kit

doi:10.18632/oncotarget.18026

Cited by 24 publications

(23 citation statements)

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“…These preliminary in vitro experimental results confirmed that P4HB may be associated with the development and progression of bladder cancer. Previous studies have demonstrated that PH4B can induce malignant tumor cell proliferation, invasion and metastasis by regulating hypoxia inducible factor-1α (HIF-1α) expression and the MAPK signaling pathway (42,43). In our present study, we found that P4HB expression was positively associated with the expression levels of ANAPC11, STRA13, and SLC397A and negatively associated with the expression levels of ZSWIM6, LYRM7, and WDR36 ( Figure 7A).…”

Section: Figure 9 |supporting

confidence: 69%

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

et al. 2020

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While hundreds of consistently altered autophagy-related genes (ARGs) have been identified in cancers, their prognostic value in bladder urothelial carcinoma (BUC) remains unclear. In the present study, we collected 232 ARGs from the Human Autophagy Database (HADb), and identified 37 differentially expressed ARGs in BUC based on The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that among the 37 differentially expressed ARGs, prolyl 4-hydroxylase, beta polypeptide (P4HB), and regulator of G protein signaling 19 (RGS19) were significantly negatively correlated with overall survival (OS) and disease-free survival (DFS). Overexpression of P4HB and RGS19 in BUC was further validated using independent data sets, including those from the Oncomine and Gene Expression Omnibus (GEO) databases. cBioPortal and UALCAN analyses indicated that altered P4HB and RGS19 mRNA expression was significantly associated with mutations and clinical characteristics (nodal metastasis and cancer stage). Moreover, co-expression network analysis and gene set enrichment analysis (GSEA) predicted that the potential functions of P4HB and RGS19 are involved in the endoplasmic reticulum (ER) stress response, cytokine-mediated signaling pathway and inflammatory response. More importantly, multivariate Cox proportional hazards regression analysis demonstrated that P4HB, but not RGS19, is an independent and unfavorable BUC biomarker based on clinical characteristics (age, gender, cancer stage, and pathological TNM stage). Finally, we validated that the mRNA and protein expression levels of P4HB were upregulated in four bladder cancer cell lines (T24, J82, EJ, and SW780) and found that knockdown of P4HB dramatically inhibited the invasion and proliferation of bladder cancer cells. In summary, our study screened ARGs and identified P4HB as a biomarker that can predict the progression and prognosis of BUC and may provide a better understanding of the autophagy regulatory mechanisms involved in BUC.

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Section: Figure 9 |supporting

confidence: 69%

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

et al. 2020

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“…24 P4HB plays a critical role in carcinogenesis in glioma, and overexpression of P4HB leads to proliferation, invasion, migration and angiogenesis in vivo and increases tumor growth through the mitogen-activated protein kinase (MAPK) signaling pathway in vitro. 25 Genetic and pharmacological inhibition of P4HB induces ERS, and early-stage ERS has protective effects on cells and promotes malignancy of tumor cells, making tumors resistant to apoptosis induced by ERS. 8 However, persistent ERS induces apoptosis to prevent tumor cells from proliferating.…”

Section: Discussionmentioning

confidence: 99%

<p>Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder</p>

Wang¹,

Bai²,

Yang³

et al. 2020

OTT

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Background: Bladder cancer (BC) is a common malignancy worldwide that accounts for 3% of global cancer diagnoses. Chemotherapy resistance limits the therapeutic effect of chemotherapeutic agents in patients with BC. Prolyl 4-hydroxylase, beta polypeptide (P4HB) is an endoplasmic reticulum (ER) chaperone that is upregulated in bladder cancer tissues (The Cancer Genome Atlas, TCGA datasets). Knockdown or suppression of P4HB exerts anticancer activity and sensitizes cells to chemotherapy in various types of cancer. Purpose: We aimed to investigate whether the inhibition of P4HB enhances the anticancer efficacy of gemcitabine (GEM) in BC cells and to study the underlying molecular mechanisms. Patients and Methods: The P4HB mRNA expression levels of 411 BC patients from the TCGA database and P4HB expression level of eighty BC paraffin-embedded samples detected by immunohistochemistry (IHC) staining were used for clinical feature and prognostic analyses. Bioinformatics analysis was utilized for the mechanistic investigation. Highly P4HB-expressed BC cell lines (T24 and 5637) treated with P4HB inhibitor (Bacitracin, BAC) were used to study the effects of BAC on the sensitivity of BC cells to GEM and the potential mechanism. P4HB inhibition experiments were performed in highly P4HB-expressed BC cells, and cell viability, colony formation, cell cycle, reactive oxygen species (ROS), apoptosis and pathway proteins were assessed in T24 and 5637 cells. Results: Western blot analysis showed that P4HB expression was significantly higher in BC tissues than in paired normal tissues. IHC showed that patients with high P4HB expression had a poorer overall survival (OS) rate than those with low P4HB expression. Furthermore, increased P4HB expression was demonstrated to be an independent prognostic marker for BC. Functionally, P4HB inhibition by BAC decreased the cell proliferation ability in vitro. Moreover, BAC treatment sensitized BC cells to GEM. Molecular mechanism analysis indicated that inhibition of P4HB by BAC treatment enhanced the anticancer effects of GEM through increasing cellular ROS content and promoting cell apoptosis and PERK/eIF2α/ATF4/CHOP signaling. Conclusion: High P4HB expression was significantly correlated with poor prognosis in BC patients. Inhibition of P4HB by BAC decreased the cell proliferation ability and sensitized BC cells to GEM by activating apoptosis and the PERK/eIF2α/ATF4/CHOP pathways.

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“…P4HB, a beta subunit of Prolyl 4-hydroxylase, might help cancer cells survive from apoptosis induced by endoplasmic reticulum (ER) stress [30,31]. P4HB promoted proliferation, invasion, migration and angiogenesis in glioma through mitogen-activated protein kinase (MAPK) signaling pathway [32]. In gastric cancer, P4HB was proved to play an important role on regulating invasion and migration in the hypoxia-inducible factor 1a (HIF1a) network [33].…”

Section: Discussionmentioning

confidence: 99%

Key Genes Associated With Prognosis and Metastasis of Clear Cell Renal Cell Carcinoma

Zhong

Jiang

Wang

et al. 2021

Preprint

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Background: Clear cell renal cell carcinoma (ccRCC) is a tumor with frequent hematogenous metastasis and is usually resistant with radiotherapy and chemotherapy. The mechanism of ccRCC metastasis still needs to be illustrated.Material and methods: The differentially expressed genes (DEGs) of three gene expression profiles (GSE85258, GSE105288 and GSE22541) downloaded from Gene Expression Omnibus (GEO) database were analyzed by GEO2R analysis, and co-expressed DEGs among them were sorted out by the online Venn drawing tool. The co-expressed DEGs were then investigated using Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and hub genes would be screened out based on protein-protein interaction network (PPI) established by STRING. After survival analysis performed on UALCAN website, possible key genes would be selected and then verified in ccRCC cell lines and ccRCC tissues (n=40). Statistical analysis of the above results was conducted using GraphPad Prism (Version 8.1.1).Results: 104 co-expressed DEGs were sorted from the three profiles. KEGG pathways revealed that these genes were enriched in the extracellular matrix (ECM)-receptor interaction, focal adhesion and PI3K-Akt signaling pathway. Survival analysis showed that among 17 hub genes, patients with higher expression of Procollagen C-Endopeptidase Enhancer (PCOLCE), Prolyl 4-Hydroxylase Subunit Beta (P4HB), Collagen Type VI Alpha 2 (COL6A2), and Collagen Type VI Alpha 3 (COL6A3) had a worse survival than those with lower expression. In vitro, the mRNA expression level of PCOLCE, P4HB and COL6A2 were 3 times, and COL6A3 16 times higher in metastatic ccRCC cell line Caki-1 than in corresponding primary cell line Caki-2. Immunohistochemistry results also showed higher expression of these 4 genes in metastatic ccRCC with statistical significance.Conclusion: PCOLCE, P4HB, COL6A2 and COL6A3 are upregulated in metastatic ccRCC and might be related to poor prognosis and distant metastases.

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

Cited by 24 publications

References 50 publications

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

<p>Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder</p>

Key Genes Associated With Prognosis and Metastasis of Clear Cell Renal Cell Carcinoma

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