P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma

Wu,Yucai; Wu,Yucai; Wu,Yucai; Wu,Yucai; Peng,Yiji; Peng,Yiji; Peng,Yiji; Peng,Yiji; Guan,Bao; Guan,Bao; Guan,Bao; Guan,Bao; He,Anbang; He,Anbang; He,Anbang; He,Anbang; Yang,Kunlin; Yang,Kunlin; Yang,Kunlin; Yang,Kunlin; He,Shiming; He,Shiming; He,Shiming; He,Shiming; Gong,Yanqing; Gong,Yanqing; Gong,Yanqing; Gong,Yanqing; Li,Xuesong; Li,Xuesong; Li,Xuesong; Li,Xuesong; Zhou,Liqun; Zhou,Liqun; Zhou,Liqun; Zhou,Liqun

doi:10.3892/ol.2020.12356

P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma

Authors:
- Yucai Wu
- Yiji Peng
- Bao Guan
- Anbang He
- Kunlin Yang
- Shiming He
- Yanqing Gong
- Xuesong Li
- Liqun Zhou
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Affiliations: Department of Urology, Peking University First Hospital, Xicheng, Beijing 100034, P.R. China
Published online on: December 6, 2020 https://doi.org/10.3892/ol.2020.12356
Article Number: 95
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A and Bray F: Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol. 71:96–108. 2017. View Article : Google Scholar : PubMed/NCBI
3	Babjuk M, Burger M, Compérat EM, Gontero P, Mostafid AH, Palou J, van Rhijn BW, Rouprêt M, Shariat SF, Sylvester R, et al: European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 76:639–657. 2019. View Article : Google Scholar : PubMed/NCBI
4	Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La Vecchia C, Shariat S, et al: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 63:234–241. 2013. View Article : Google Scholar : PubMed/NCBI
5	Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, Hernández V, Espinós EL, Dunn J, Rouanne M, et al: Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 71:462–475. 2017. View Article : Google Scholar : PubMed/NCBI
6	Parakh S and Atkin JD: Novel roles for protein disulphide isomerase in disease states: A double edged sword? Front Cell Dev Biol. 3:302015. View Article : Google Scholar : PubMed/NCBI
7	Zhang J, Guo S, Wu Y, Zheng ZC, Wang Y and Zhao Y: P4HB, a novel hypoxia target gene related to gastric cancer invasion and metastasis. BioMed Res Int. 2019:97497512019.PubMed/NCBI
8	Zhou Y, Yang J, Zhang Q, Xu Q, Lu L, Wang J and Xia W: P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling. Mol Med Rep. 19:231–237. 2019.PubMed/NCBI
9	Zhu Z, He A, Lv T, Xu C, Lin L and Lin J: Overexpression of P4HB is correlated with poor prognosis in human clear cell renal cell carcinoma. Cancer Biomark. 26:431–439. 2019. View Article : Google Scholar : PubMed/NCBI
10	Sun S, Lee D, Ho AS, Pu JK, Zhang XQ, Lee NP, Day PJ, Lui WM, Fung CF and Leung GK: Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways. Neuro Oncol. 15:562–577. 2013. View Article : Google Scholar : PubMed/NCBI
11	Lee D, Sun S, Zhang XQ, Zhang PD, Ho AS, Kiang KM, Fung CF, Lui WM and Leung GK: MicroRNA-210 and endoplasmic reticulum chaperones in the regulation of chemoresistance in glioblastoma. J Cancer. 6:227–232. 2015. View Article : Google Scholar : PubMed/NCBI
12	Liu Y, Ji W, Shergalis A, Xu J, Delaney AM, Calcaterra A, Pal A, Ljungman M, Neamati N and Rehemtulla A: Activation of the unfolded protein response via inhibition of protein disulfide isomerase decreases the capacity for DNA repair to sensitize glioblastoma to radiotherapy. Cancer Res. 79:2923–2932. 2019. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Goldman MJ, Craft B, Hastie M, Repečka K, McDade F, Kamath A, Banerjee A, Luo Y, Rogers D, Brooks AN, et al: Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol. 38:675–678. 2020. View Article : Google Scholar : PubMed/NCBI
15	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
16	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
17	Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al: STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43:D447–D452. 2015. View Article : Google Scholar : PubMed/NCBI
18	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
19	Subramanian A, Kuehn H, Gould J, Tamayo P and Mesirov JP: GSEA-P: A desktop application for Gene Set Enrichment Analysis. Bioinformatics. 23:3251–3253. 2007. View Article : Google Scholar : PubMed/NCBI
20	Hatahet F and Ruddock LW: Substrate recognition by the protein disulfide isomerases. FEBS J. 274:5223–5234. 2007. View Article : Google Scholar : PubMed/NCBI
21	Freedman RB, Hirst TR and Tuite MF: Protein disulphide isomerase: Building bridges in protein folding. Trends Biochem Sci. 19:331–336. 1994. View Article : Google Scholar : PubMed/NCBI
22	Wilson R, Lees JF and Bulleid NJ: Protein disulfide isomerase acts as a molecular chaperone during the assembly of procollagen. J Biol Chem. 273:9637–9643. 1998. View Article : Google Scholar : PubMed/NCBI
23	Moon HW, Han HG and Jeon YJ: Protein quality control in the endoplasmic reticulum and cancer. Int J Mol Sci. 19:30202018. View Article : Google Scholar
24	Cubillos-Ruiz JR, Bettigole SE and Glimcher LH: Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell. 168:692–706. 2017. View Article : Google Scholar : PubMed/NCBI
25	Xie L, Li H, Zhang L, Ma X, Dang Y, Guo J, Liu J, Ge L, Nan F, Dong H, et al: Autophagy-related gene P4HB: A novel diagnosis and prognosis marker for kidney renal clear cell carcinoma. Aging (Albany NY). 12:1828–1842. 2020. View Article : Google Scholar : PubMed/NCBI
26	Lovat PE, Corazzari M, Armstrong JL, Martin S, Pagliarini V, Hill D, Brown AM, Piacentini M, Birch-Machin MA and Redfern CP: Increasing melanoma cell death using inhibitors of protein disulfide isomerases to abrogate survival responses to endoplasmic reticulum stress. Cancer Res. 68:5363–5369. 2008. View Article : Google Scholar : PubMed/NCBI
27	Peng Z, Chen Y, Cao H, Zou H, Wan X, Zeng W, Liu Y, Hu J, Zhang N, Xia Z, et al: Protein disulfide isomerases are promising targets for predicting the survival and tumor progression in glioma patients. Aging (Albany NY). 12:2347–2372. 2020. View Article : Google Scholar : PubMed/NCBI
28	Oliveira-Ferrer L, Legler K and Milde-Langosch K: Role of protein glycosylation in cancer metastasis. Semin Cancer Biol. 44:141–152. 2017. View Article : Google Scholar : PubMed/NCBI
29	Contessa JN, Bhojani MS, Freeze HH, Ross BD, Rehemtulla A and Lawrence TS: Molecular imaging of N-linked glycosylation suggests glycan biosynthesis is a novel target for cancer therapy. Clin Cancer Res. 16:3205–3214. 2010. View Article : Google Scholar : PubMed/NCBI
30	Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A and Lawrence TS: Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res. 68:3803–3809. 2008. View Article : Google Scholar : PubMed/NCBI