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.

Kaynakça

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.

Kaynak Göster