Protein disulfide isomerases are promising targets for predicting the survival and tumor progression in glioma patients

Peng, Zhigang; Chen, Yu; Cao, Hui; Zou, Hecun; Wan, Xin; Zeng, Wenjing; Liu, Yanling; Hu, Jiaqing; Zhang, Nan; Xia, Zhiwei; Liu, Zhixiong; Cheng, Quan

doi:10.18632/aging.102748

Cited by 29 publications

(24 citation statements)

References 52 publications

(60 reference statements)

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“…P4HB, also known as PDIA1, PDI or CLCRP1, is a vital disulfide isomerase, redox enzyme and chaperone in the ER and is regarded as a prognostic factor related to the genesis and progression of multiple carcinomas. [20][21][22] However, the correlation between P4HB and BC remains unclear. Our study demonstrated for the first time that the expression of P4HB was elevated in BC tissues from 80 patients and BC cell lines, which was consistent with results from the TCGA database analysis.…”

Section: Discussionmentioning

confidence: 99%

“…In previously published studies, P4HB and PDIA3 played an important role in diffuse glioma progression and therapeutic outcomes, 23 and the PDI family is associated with the survival and tumor progression of glioma. 22 Moreover, recent research revealed that high P4HB expression is correlated with poor prognosis in hepatocellular carcinoma 15 and could be a potential prognostic biomarker in gastric cancer. 20 P4HB is highly expressed in renal clear cell carcinoma (ccRCC) and positively correlated with pathological grade, stage and poor prognosis; it has been verified as an independent risk factor by multifactor Cox regression in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

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<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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Section: Discussionmentioning

confidence: 99%

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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“…Using “GSVA package”, functional enrichment analysis was performed as previously described [ 30 ] to reveal the mechanisms of action of the aging-related genes in the initiation and progression of gliomas.…”

Section: Methodsmentioning

confidence: 99%

Aging-related genes are potential prognostic biomarkers for patients with gliomas

Xiao

Zhang

et al. 2021

Aging

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“…Lovat et al ( 26 ) demonstrated that overexpression of wild-type P4HB in melanoma cells decreased the level of apoptosis in response to ER stress, which was beneficial to the survival of tumor cells. Furthermore, recent studies have demonstrated that P4HB is overexpressed in gliomas and that P4HB suppression sensitizes glioblastoma to chemotherapy and radiotherapy by abrogating ER stress-induced UPR signaling ( 10 , 12 , 27 ). These results suggested the clinical importance of P4HB in tumorigenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma

Peng

Guan

et al. 2020

Oncol Lett

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Prolyl 4-hydroxylase, beta polypeptide (P4HB) protein is an endoplasmic reticulum (ER) molecular chaperone protein and has been reported to be overexpressed in multiple tumor types. However, the role of P4HB in bladder cancer (BLCA) has not yet been elucidated. The aim of the present study was to investigate the prognostic value of P4HB and the association between clinicopathological characteristics and P4HB in BLCA. P4HB expression levels were assessed through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis in BLCA tissues and cells. A total of 69 pairs of tumor and normal samples were used to analyze the expression of P4HB via immunohistochemical staining. A co-expression network and functional enrichment analyses were conducted to investigate the biological function of P4HB in BLCA. The protein-protein interaction (PPI) network was constructed by Search Tool for the Retrieval of Interacting Genes. The results showed that P4HB was highly expressed in BLCA cells and tissues. The area under the curve value for P4HB expression to discriminate between tumor and normal tissues was up to 0.888 (95% CI: 0.801–0.975; P<0.001) and 0.881 (95% CI: 0.825–0.937; P<0.001) in TCGA database and our database, respectively. Furthermore, the expression level of P4HB was an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) by univariate and multivariate analyses. Kaplan-Meier survival analysis demonstrated that high P4HB expression was associated with low OS and RFS. Pathway enrichment analysis suggested that P4HB was involved in protein processing in the endoplasmic reticulum (ER), including N-glycan modification and protein metabolic processes responding to ER stress. PPI analysis revealed that the potential targets of P4HB were mainly involved in posttranslational protein modification and response to ER stress. In conclusion, the expression level of P4HB aid in identifying patients with early-stage BLCA and predicting the prognosis of BLCA. Therefore, P4HB may be a novel diagnostic and prognostic biomarker for BLCA.

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Protein disulfide isomerases are promising targets for predicting the survival and tumor progression in glioma patients

Cited by 29 publications

References 52 publications

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

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

Aging-related genes are potential prognostic biomarkers for patients with gliomas

P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma

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