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Identification and Characterization of Biomarkers and Their Functions for Docetaxel‑Resistant Prostate Cancer Cells

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Identification and Characterization of Biomarkers and Their Functions for Docetaxel‑Resistant Prostate Cancer Cells 3236 ONCOLOGY LETTERS 18: 3236-3248, 2019 Identification and characterization of biomarkers and their functions for docetaxel‑resistant prostate cancer cells LEIHONG DENG1, XIAOPENG GU2, TAO ZENG3, FANGHUA XU4, ZHIFENG DONG1, CHAO LIU1 and HAICHAO CHAO5 1Medical Department of The Graduate School, Nanchang University, Nanchang, Jiangxi 330006; 2Department of Orthopedics, Zhoushan Guhechuan Hospital, Zhoushan, Zhejang 316000; 3Department of Urology, 4Pathology Department, 5Laboratory of Clinical Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China Received November 3, 2018; Accepted June 13, 2019 DOI: 10.3892/ol.2019.10623 Abstract. Docetaxel treatment is a standard chemotherapy (ICAM1), interleukin (IL)6, CXC motif chemokine ligand 8 strategy for castration-resistant prostate cancer (CRPC), (CXCL8), cyclin dependent kinase 1 and CD44 molecule and patients with CRPC eventually develop resistance to (CD44) were significantly differentially expressed in prostate treatment. However, little is understood regarding the under- cancer tissues compared with healthy tissues based on The lying mechanism of resistance. The present study aimed Cancer Genome Atlas data. The Gene Expression Profiling to identify the underlying crucial genes and regulatory Interactive Analysis database revealed that ICAM1 was networks associated with docetaxel resistance in prostate positively associated with IL6 and CXCL8, and epidermal cancer using bioinformatics analyses. For this purpose, one growth factor receptor was positively associated with CD44 expression profile dataset (GSE33455), which included two and SYK. Additionally, ten hub genes, which were identi- docetaxel-sensitive and two docetaxel-resistant cell lines, was fied to be associated with the drug resistance of docetaxel downloaded from the Gene Expression Omnibus database, in prostatic carcinoma in the present study, were predomi- and analyses of differential gene expression and function nantly associated with tumor progression and metastasis. enrichment were performed. A protein-protein interaction Reverse transcription-quantitative PCR analysis performed (PPI) network was constructed, and the associated hub genes on docetaxel-sensitive and docetaxel-resistant prostate cancer were investigated using the Search Tool for the Retrieval of cell lines demonstrated that certain hub genes, including Interacting Genes/Proteins and Cytoscape software. A total CDK1, 2'‑5'‑oligoadenylate synthetase 3, CXCL8 and CDH1, of 756 differentially expression genes (DEGs) were identified, were highly expressed in the docetaxel-resistant cell lines, including 509 downregulated and 247 upregulated genes. which confirmed the bioinformatics results. In conclusion, the Enrichment analysis revealed that the DEGs were associated present study identified a number of important genes that are with the interferon-γ-mediated signaling pathway, protein associated with the molecular mechanism of docetaxel resis- binding, bicellular tight junctions and cancer pathways. tance by integrated bioinformatical analysis, and these genes Two modules were screened from the PPI network, and the and regulatory networks may assist with identifying potential corresponding genes were identified to be largely enriched in gene therapy targets for CRPC. Further functional analyses the interferon-γ-mediated signaling pathway and the negative are required to validate the current findings. regulators of the DExD/H‑Box helicase 58/interferon induced with helicase C domain 1 signaling pathway, and enriched in Introduction cell-cell adhesion and the Rap1 signaling pathway. Among the ten hub genes, epidermal growth factor receptor, spleen Prostate cancer (PCa), which exhibits complicated pathogen- tyrosine kinase (SYK), intracellular adhesion molecule 1 esis and treatment difficulties, is the most common malignancy of the male reproductive system worldwide, accounting for ~29,430 deaths in the USA in 2018 (1). PCa is a global public issue that threatens human health and life, with increasing morbidity and mortality rates each year (2). Metastatic PCa Correspondence to: Dr Haichao Chao, Laboratory of Clinical Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang is commonly treated with androgen deprivation therapy; University, 152 Ai‑Guo Road, Nanchang, Jiangxi 330006, P.R. China however, resistance can still develop quickly, which leads E-mail: [email protected] to castration-resistant PCa (CRPC) (3). Docetaxel is widely used as the standard first-line chemotherapy treatment for Key words: docetaxel-resistant, prostate cancer, differentially patients with CRPC (3). The majority of patients with CRPC expressed genes, protein-protein interaction network, hub genes who receive docetaxel chemotherapy develop resistance to this treatment. Additionally, with increasing treatment times and doses, complications may occur (4). Therefore, further DENG et al: Screening for huB genes of docetaxel-resistant prostate cancer 3237 investigation regarding the mechanism of docetaxel-resistant (docetaxel‑sensitive), PC‑3 (docetaxel‑sensitive), DU‑145R PCa may improve the prognosis of patients with PCa. (docetaxel-resistant) and PC-3R (docetaxel-resistant). Although the mechanism underlying PCa drug resistance has been extensively studied, its cause and pathogenesis Analysis of DEGs. The original expression data underwent remain poorly understood. The current consensus is that the background correction and quartile data normalization and was mechanism of docetaxel-resistant PCa is associated with converted into gene expression measures using the robust multi- multiple factors, including androgen receptor splice variant array average (14) in the R Affy package (release 3.9; http://www. expression (5), changes in the expression of β-tubulin (6), bioconductor.org/packages/release/bioc/html/affy.html). The multidrug resistance induced by abnormal expression of the DEGs between docetaxel-sensitive and docetaxel-resistant ATP binding cassette (ABC) transporter family and abnormal samples were analyzed using the limma package (15) in expression of signaling pathway factors (7), including the Bioconductor (http://www.bioconductor.org), and a DEG was PI3K/AKT/mTOR (8), Wnt (9) and NF-κB/interleukin (IL)6 considered to be significant according to the following criteria: pathways (10). Additionally, abnormal expression levels of |log[fold‑change (FC)]|>2 and false discovery rate (FDR) EMT and stem-like cell markers have been detected in PCa <0.05. Subsequently, a heatmap was constructed and the DEGs cells resistant to docetaxel, which lead to a downregulation were identified using the pheatmap package of R software (16). of cadherin 1 (CDH1) and an upregulation of vimentin, zinc finger E-box binding homeobox 1 and the stem-like cell Gene ontology (GO) and Kyoto Encyclopedia of Genes and marker CD44 molecule (CD44) (11). Taken together, these Genomes (KEGG) pathway analyses. GO is a tool used to studies suggest that docetaxel resistance in PCa occurs due to annotate genes, collect and analyze information according to alterations in numerous factors and/or genetic changes, rather cellular component (CC), biological process (BP) and molec- than a single factor. Although these basic and clinical studies ular function (MF) terms following the criteria P<0.05 (17). have investigated the resistance of docetaxel in PCa in the past KEGG is an online database and analysis tool for integrating few decades with the aim of revealing the potential underlying and interpreting large molecular datasets (18). Database mechanisms, the effect of treatment remains unsatisfac- for Annotation, Visualization and Integrated Discovery tory (5‑11). Therefore, understanding the precise molecular (DAVID; https://david.ncifcrf.gov) is a website composed of mechanisms associated with the development of docetaxel a comprehensive biological database and analysis tools that resistance in PCa is essential for the improvement of effective assist with the understanding of the biological meaning of diagnosis and treatment strategies. Microarray technologies, gene lists (19). In the present study, DAVID and Metascape which have widely been used to investigate large scale gene (https://metascape.org) were used for GO and KEGG pathway expression simultaneously, presents an effective method to enrichment analyses of the DEGs. FDR<0.05 was considered investigate the expression of tens of thousands of genes and to indicate a statistically significant result. identify the mechanisms of numerous diseases, particularly cancers. The integration and analysis of microarray data Analysis of the PPI network. The STRING database is an provide valuable information for the study of docetaxel online biological database that collects comprehensive infor- resistance (12). mation on proteins to evaluate the PPI information (20). In the In this present study, the GSE33455 microarray current study, significant gene pairs of the PPI network were dataset (13), which includes two docetaxel-sensitive and two visually represented using Cytoscape; a combined score >0.4 docetaxel-resistant cell lines, was downloaded from the Gene was considered as significant and the strength of an interac- Expression Omnibus (GEO) database, and differentially tion was modelled by the number of lines (21). Cytoscape expressed genes (DEGs) between the two types of PCa cell is a bioinformatics software used to perform computational lines were identified. Functional enrichment
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