Assessment of Molecular Mechanisms and Potential Biomarkers in Bladder Urothelial Carcinoma

Objective: Bladder cancer ranks 10th among the most common cancers worldwide, effecting mostly man than women. The aim of this study is to perform a detailed gene expression analysis of bladder urothelial carcino-ma to reveal altered molecular mechanisms and to find potential biomark-ers for this cancer. Materials and Methods: Bladder urothelial carcinoma RNA-seq data from TCGA with normal bladder samples from GTEx were analyzed by using GEPIA. Differentially expressed genes were annotated to GO-BP and KEGG pathway terms with DAVID and PPI networks were constructed by STRING. The association of upregulated cell cycle pathway proteins and patient sur-vival was further investigated. Results: Upregulated genes mainly annotated to cell cycle, p53 signaling and oocyte meiosis and maturation pathways and cell cycle related GO-BP terms. Downregulated genes mostly annotated to adhesion, ECM-receptor inter-action, vascular smooth muscle contraction and cardiomyopathy related KEGG pathways and muscle related GO-BP terms. The protein products of six cell cycle genes, which were upregulated in bladder urothelial carcinoma, showed significant association with patient survival. Conclusion: The results of this study showed altered molecular mechanisms and increased our understanding of bladder urothelial carcinoma, proposed potential prognostic biomarkers.

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Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statis-tics 2018: GLOBOCAN estimates of incidence and mortali-ty worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424.

Shinagare AB, Ramaiya NH, Jagannathan JP, et al. Metastatic pattern of bladder cancer: correlation with the characteristics of the primary tumor. AJR Am J Roentgenol 2011; 196: 117-22.

Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013; 63: 23 4 - 41.

Zhang X, Zhang Y. Bladder Cancer and Genetic Mutations. Cell Biochem Biophys 2015; 73: 65-9.

Tang F, He Z, Lei H, et al. Identification of differentially ex-pressed genes and biological pathways in bladder cancer. Mol Med Rep 2018; 17: 6425-34.[

Di Y, Chen D, Yu W, et al. Bladder cancer stage-associat-ed hub genes revealed by WGCNA co-expression network analysis. Hereditas 2019; 156: 7.

Yan M, Jing X, Liu Y, et al. Screening and identification of key biomarkers in bladder carcinoma: Evidence from bio-informatics analysis. Oncol Lett 2018; 16: 3092-100.

Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2017; 171: 540-56 e25.

Choi W, Ochoa A, McConkey DJ, et al. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset. Eur Urol 2017; 72: 354-65.

Cancer Genome Atlas Research N. Comprehensive mo-lecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315-22.

Glaser AP, Fantini D, Wang Y, et al. APOBEC-mediated mu-tagenesis in urothelial carcinoma is associated with im-proved survival, mutations in DNA damage response genes, and immune response. Oncotarget 2018; 9: 4537- 48.

Gao JM, Huang LZ, Huang ZG, et al. Clinical value and po-tential pathways of miR-183-5p in bladder cancer: A study based on miRNA-seq data and bioinformatics analysis. Oncol Lett 2018; 15: 5056-70.

He RQ, Huang ZG, Li TY, et al. RNA-Sequencing Data Reveal a Prognostic Four-lncRNA-Based Risk Score for Bladder Urothelial Carcinoma: An in Silico Update. Cell Physiol Biochem 2018; 50: 1474-95.

Tang Z, Li C, Kang B, et al. GEPIA: a web server for can-cer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45: W98-W102.

Huang da W, Sherman BT, Lempicki RA. Bioinformatics en-richment tools: paths toward the comprehensive func-tional analysis of large gene lists. Nucleic Acids Res 2009; 37: 1-13.

Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44-57.

Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: pro-tein-protein association networks with increased cover-age, supporting functional discovery in genome-wide ex-perimental datasets. Nucleic Acids Res 2019; 47: D607-D13.

Nagy A, Lanczky A, Menyhart O, et al. Validation of miR-NA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep 2018; 8: 9 2 2 7.

Jinka R, Kapoor R, Sistla PG, et al. Alterations in Cell-Extracellular Matrix Interactions during Progression of Cancers. Int J Cell Biol 2012; 2012: 219196.

Herrmann J, Lerman A, Sandhu NP, et al. Evaluation and management of patients with heart disease and cancer: cardio-oncology. Mayo Clin Proc 2014; 89: 1287-306.

Chai N, Xie HH, Yin JP, et al. FOXM1 promotes prolifera-tion in human hepatocellular carcinoma cells by transcrip-tional activation of CCNB1. Biochem Biophys Res Commun 2018; 500: 924-9.

Fang Y, Yu H, Liang X, et al. Chk1-induced CCNB1 overex-pression promotes cell proliferation and tumor growth in human colorectal cancer. Cancer Biol Ther 2014; 15: 126 8 -79.

Ouellet V, Guyot MC, Le Page C, et al. Tissue array analysis of expression microarray candidates identifies markers as-sociated with tumor grade and outcome in serous epithe-lial ovarian cancer. Int J Cancer 2006; 119: 599-607.

Wang Z, Wan L, Zhong J, et al. Cdc20: a potential novel therapeutic target for cancer treatment. Curr Pharm Des 2013; 19: 3210-4.

Gao X, Chen Y, Chen M, et al. Identification of key candi-date genes and biological pathways in bladder cancer. PeerJ 2018; 6: e6036.

Yuan B, Xu Y, Woo JH, et al. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosom-al instability. Clin Cancer Res 2006; 12: 405-10.

Zhang Z, Zhang G, Gao Z, et al. Comprehensive analysis of differentially expressed genes associated with PLK1 in bladder cancer. BMC Cancer 2017; 17: 861.

Zhang Z, Zhang G, Kong C. High expression of polo-like kinase 1 is associated with the metastasis and recurrence in urothelial carcinoma of bladder. Urol Oncol 2013; 31: 1222-30.

Xiang W, Wu X, Huang C, et al. PTTG1 regulated by miR-146a-3p promotes bladder cancer migration, invasion, metastasis and growth. Oncotarget 2017; 8: 664-78.

Pineda S, Milne RL, Calle ML, et al. Genetic variation in the TP53 pathway and bladder cancer risk. a comprehensive analysis. PLoS One 2014; 9: e89952.

Negraes PD, Favaro FP, Camargo JL, et al. DNA methylation patterns in bladder cancer and washing cell sediments: a perspective for tumor recurrence detection. BMC Cancer 2008; 8: 238.