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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Metastasis | Primary research

Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

Authors: Ping-Bao Zhang, Zi-Li Huang, Yong-Hua Xu, Jin Huang, Xin-Yu Huang, Xiu-Yan Huang

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice.

Methods

This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways.

Results

In the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC.

Conclusions

In summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.
Appendix
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Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424.CrossRef
2.
Dobruch J, Daneshmand S, Fisch M, Lotan Y, Noon AP, Resnick MJ, Shariat SF, Zlotta AR, Boorjian SA. Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur Urol. 2016;69(2):300–10.CrossRefPubMed
3.
Hanna KS. A review of immune checkpoint inhibitors for the management of locally advanced or metastatic urothelial carcinoma. Pharmacotherapy. 2017;37(11):1391–405.CrossRefPubMed
4.
5.
Gakis G, Stenzl A. Gender-specific differences in muscle-invasive bladder cancer: the concept of sex steroid sensitivity. World J Urol. 2013;31(5):1059–64.CrossRefPubMed
6.
Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, Seminara D, Yoshida T, Saeki N, Andrew AS, et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet. 2009;41(9):991–5.CrossRefPubMedPubMedCentral
7.
Hurst CD, Platt FM, Taylor CF, Knowles MA. Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis. Clin Cancer Res. 2012;18(21):5865–77.CrossRefPubMedPubMedCentral
8.
Kim WJ, Kim SK, Jeong P, Yun SJ, Cho IC, Kim IY, Moon SK, Um HD, Choi YH. A four-gene signature predicts disease progression in muscle invasive bladder cancer. Mol Med. 2011;17(5–6):478–85.CrossRefPubMedPubMedCentral
9.
Kim YH, Kim WT, Jeong P, Ha YS, Kang HW, Yun SJ, Moon SK, Choi YH, Kim IY, Kim WJ. Novel combination markers for predicting survival in patients with muscle invasive bladder cancer: USP18 and DGCR2. J Korean Med Sci. 2014;29(3):351–6.CrossRefPubMedPubMedCentral
10.
Wu J, Wan F, Sheng H, Shi G, Shen Y, Lin G, Dai B, Zhu Y, Ye D. NR1H3 expression is a prognostic factor of overall survival for patients with muscle-invasive bladder cancer. J Cancer. 2017;8(5):852–60.CrossRefPubMedPubMedCentral
11.
Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556.e525.CrossRefPubMedPubMedCentral
12.
Goldman M, Craft B, Brooks A, Zhu J, Haussler D. The UCSC Xena Platform for cancer genomics data visualization and interpretation. bioRxiv. 2018:326470.
13.
El Behi M, Krumeich S, Lodillinsky C, Kamoun A, Tibaldi L, Sugano G, De Reynies A, Chapeaublanc E, Laplanche A, Lebret T, et al. An essential role for decorin in bladder cancer invasiveness. EMBO Mol Med. 2013;5(12):1835–51.CrossRefPubMedPubMedCentral
14.
Parkinson H, Kapushesky M, Shojatalab M, Abeygunawardena N, Coulson R, Farne A, Holloway E, Kolesnykov N, Lilja P, Lukk M, et al. ArrayExpress—a public database of microarray experiments and gene expression profiles. Nucleic Acids Res. 2007;35(Database issue):D747–50.CrossRefPubMed
15.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41(Database issue):D991–5.PubMed
16.
Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65.CrossRefPubMedPubMedCentral
17.
18.
Sergushichev AA. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv. 2016:060012.
19.
Lagani V, Athineou G, Farcomeni A, Tsagris M, Tsamardinos I. Feature selection with the r package mxm: discovering statistically-equivalent feature subsets. arXiv preprint arXiv:​161103227. 2016.
20.
Cotto KC, Wagner AH, Feng YY, Kiwala S, Coffman AC, Spies G, Wollam A, Spies NC, Griffith OL, Griffith M. DGIdb 3.0: a redesign and expansion of the drug–gene interaction database. Nucleic Acids Res. 2018;46(D1):D1068–73.CrossRefPubMed
21.
Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.CrossRefPubMedPubMedCentral
22.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.CrossRefPubMedPubMedCentral
23.
Zhou H, Zhang Y, Wu L, Xie W, Li L, Yuan Y, Chen Y, Lin Y, He X. Elevated transgelin/TNS1 expression is a potential biomarker in human colorectal cancer. Oncotarget. 2018;9(1):1107–13.CrossRefPubMed
24.
Zhou HM, Fang YY, Weinberger PM, Ding LL, Cowell JK, Hudson FZ, Ren M, Lee JR, Chen QK, Su H, et al. Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility. BMC Cancer. 2016;16:55.CrossRefPubMedPubMedCentral
25.
Senbabaoglu Y, Gejman RS, Winer AG, Liu M, Van Allen EM, de Velasco G, Miao D, Ostrovnaya I, Drill E, Luna A, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 2016;17(1):231.CrossRefPubMedPubMedCentral
26.
White NM, Mathews M, Yousef GM, Prizada A, Popadiuk C, Dore JJ. KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma. Br J Cancer. 2009;101(7):1107–13.CrossRefPubMedPubMedCentral
27.
Schrader CH, Kolb M, Zaoui K, Flechtenmacher C, Grabe N, Weber KJ, Hielscher T, Plinkert PK, Hess J. Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients. Mol Cancer. 2015;14:107.CrossRefPubMedPubMedCentral
28.
Chen Y, Zhao J, Li D, Hao J, He P, Wang H, Zhang M. TRIM56 suppresses multiple myeloma progression by activating TLR3/TRIF signaling. Yonsei Med J. 2018;59(1):43–50.CrossRefPubMed
29.
Zhao L, Zhang P, Su XJ, Zhang B. The ubiquitin ligase TRIM56 inhibits ovarian cancer progression by targeting vimentin. J Cell Physiol. 2018;233(3):2420–5.CrossRefPubMed
30.
31.
Eke I, Cordes N. Focal adhesion signaling and therapy resistance in cancer. Semin Cancer Biol. 2015;31:65–75.CrossRefPubMed
32.
33.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.CrossRefPubMed
34.
Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, Deryugina EI. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood. 2013;122(25):4054–67.CrossRefPubMedPubMedCentral
35.
Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 2014;17(1):109–18.CrossRefPubMed
36.
Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014;5:75.CrossRefPubMedPubMedCentral
Metadata
Title
Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer
Authors
Ping-Bao Zhang
Zi-Li Huang
Yong-Hua Xu
Jin Huang
Xin-Yu Huang
Xiu-Yan Huang
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Metastasis
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-1056-y

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