Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-11-2019 | Original Article – Cancer Research

MicroRNAs in tumor samples and urinary extracellular vesicles as a putative diagnostic tool for muscle-invasive bladder cancer

Authors: Sophie Baumgart, Pascal Meschkat, Philipp Edelmann, Joana Heinzelmann, Alexey Pryalukhin, Rainer Bohle, Julia Heinzelbecker, Michael Stöckle, Kerstin Junker

Published in: Journal of Cancer Research and Clinical Oncology | Issue 11/2019

Abstract

Purpose

The identification of biomarkers characterizing the invasive potential of bladder cancer could enhance the clinical management of individual patients and therefore improve prognosis. The aim of this study was to define a miRNA panel in tumor tissues as well as in urinary extracellular vesicles (EVs) for discriminating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC).

Methods

miRNA expression was analyzed in 24 formalin-fixed, paraffin-embedded (FFPE) tumor samples by microarray analysis and was further validated by qRT-PCR in 56 FFPE tumor samples as well as in 37 urinary EV samples.

Results

Microarray analysis revealed 63 miRNAs that were significantly differentially expressed (P < 0.05) between tissues from MIBC and NMIBC tumors. Five selected miRNAs (miR-146b-5p, miR-155-5p, miR-138-5p, miR-144-5p, and miR-200a-3p) were validated by qRT-PCR. The expression of all except miR-144-5p was significantly associated with high tumor grade. In urinary EVs, a different expression was verified for miR-146b-5p (P = 0.004) and miR-155-5p (P = 0.036), which exhibited significantly higher expression in urinary EVs from patients with MIBC.

Conclusions

miRNAs are promising biomarkers for the identification of invasive bladder carcinomas. Tissue samples as well as urinary EVs may serve as sources for miRNA analysis. This method, in addition to histopathology, could provide a new diagnostic tool and facilitate individual therapeutic decisions to select patients for early cystectomy.

Adam L, Wszolek MF, Liu CG, Jing W, Diao L, Zien A, Zhang JD, Jackson D, Dinney CP (2013) Plasma microRNA profiles for bladder cancer detection. Urol Oncol 31:1701–1708CrossRef

Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71:447–461CrossRef

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRef

Baumgart S, Heinzelmann J, Krause E, Stöckle M, Stampe Ostenfeld M, Junker K (2017a) Tumor-associated exosomes of urothelial bladder cancer cells affect tumor-promoting processes in normal bladder fibroblasts and support tumorigenesis. Eur Urol Suppl 16:e897CrossRef

Baumgart S, Holters S, Ohlmann CH, Bohle R, Stockle M, Ostenfeld MS, Dyrskjot L, Junker K, Heinzelmann J (2017b) Exosomes of invasive urothelial carcinoma cells are characterized by a specific miRNA expression signature. Oncotarget 8:58278–58291CrossRef

Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One 9:e95240CrossRef

Cho JA, Park H, Lim EH, Lee KW (2012) Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol 40:130–138CrossRef

Corrado C, Raimondo S, Chiesi A, Ciccia F, De Leo G, Alessandro R (2013) Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 14:5338–5366CrossRef

Deng X, Wu B, Xiao K, Kang J, Xie J, Zhang X, Fan Y (2015) MiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3. Cell Physiol Biochem 35:71–82CrossRef

Dyrskjot L, Ostenfeld MS, Bramsen JB, Silahtaroglu AN, Lamy P, Ramanathan R, Fristrup N, Jensen JL, Andersen CL, Zieger K, Kauppinen S, Ulhoi BP, Kjems J, Borre M, Orntoft TF (2009) Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Can Res 69:4851–4860CrossRef

Eble JN, Sauter G, Epstein JI, Sesterhenn IA (2004) WHO classification of tumours. Pathology and genetics of tumours of the urinary system and male genital organs. IARC Press, Lyon

Edge S, Byrd DR, Compton CC, Fritz AG, Greene F, Trotti A (2010) AJCC cancer staging handbook. Springer, New York

Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273:20121–20127CrossRef

Fevrier B, Raposo G (2004) Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol 16:415–421CrossRef

Gao Y, Ma X, Yao Y, Li H, Fan Y, Zhang Y, Zhao C, Wang L, Ma M, Lei Z, Zhang X (2016) miR-155 regulates the proliferation and invasion of clear cell renal cell carcinoma cells by targeting E2F2. Oncotarget 7:20324–20337PubMedPubMedCentral

Jiang X, Du L, Wang L, Li J, Liu Y, Zheng G, Qu A, Zhang X, Pan H, Yang Y, Wang C (2015) Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int J Cancer 136:854–862CrossRef

Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15:25–41CrossRef

Koga Y, Yasunaga M, Moriya Y, Akasu T, Fujita S, Yamamoto S, Matsumura Y (2011) Exosome can prevent RNase from degrading microRNA in feces. J Gastrointest Oncol 2:215–222PubMedPubMedCentral

Le XF, Merchant O, Bast RC, Calin GA (2010) The roles of MicroRNAs in the cancer invasion-metastasis cascade. Cancer Microenviron 3:137–147CrossRef

Matsuzaki K, Fujita K, Jingushi K, Kawashima A, Ujike T, Nagahara A, Ueda Y, Tanigawa G, Yoshioka I, Ueda K, Hanayama R, Uemura M, Miyagawa Y, Tsujikawa K, Nonomura N (2017) MiR-21-5p in urinary extracellular vesicles is a novel biomarker of urothelial carcinoma. Oncotarget 8:24668–24678CrossRef

Mellman I (1996) Endocytosis and molecular sorting. Annu Rev Cell Dev Biol 12:575–625CrossRef

Pignot G, Cizeron-Clairac G, Vacher S, Susini A, Tozlu S, Vieillefond A, Zerbib M, Lidereau R, Debre B, Amsellem-Ouazana D, Bieche I (2013) microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer. Int J Cancer J Int Cancer 132:2479–2491CrossRef

Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, Castro MAA, Gibb EA, Kanchi RS, Gordenin DA, Shukla SA, Sanchez-Vega F, Hansel DE, Czerniak BA, Reuter VE, Su X, de Sa Carvalho B, Chagas VS, Mungall KL, Sadeghi S, Pedamallu CS, Lu Y, Klimczak LJ, Zhang J, Choo C, Ojesina AI, Bullman S, Leraas KM, Lichtenberg TM, Wu CJ, Schultz N, Getz G, Meyerson M, Mills GB, McConkey DJ, Weinstein JN, Kwiatkowski DJ, Lerner SP (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171(540–556):e525

Song T, Xia W, Shao N, Zhang X, Wang C, Wu Y, Dong J, Cai W, Li H (2010) Differential miRNA expression profiles in bladder urothelial carcinomas. Asian Pac J Cancer Prev 11:905–911PubMed

Sun DK, Wang JM, Zhang P, Wang YQ (2015) MicroRNA-138 regulates metastatic potential of bladder cancer through ZEB2. Cell Physiol Biochem 37:2366–2374CrossRef

Wang G, Chan ES, Kwan BC, Li PK, Yip SK, Szeto CC, Ng CF (2012) Expression of microRNAs in the urine of patients with bladder cancer. Clin Genitourin Cancer 10:106–113CrossRef

Yang R, Liu M, Liang H, Guo S, Guo X, Yuan M, Lian H, Yan X, Zhang S, Chen X, Fang F, Guo H, Zhang C (2016) miR-138-5p contributes to cell proliferation and invasion by targeting survivin in bladder cancer cells. Mol Cancer 15:82CrossRef

Title: MicroRNAs in tumor samples and urinary extracellular vesicles as a putative diagnostic tool for muscle-invasive bladder cancer
Authors: Sophie Baumgart
Pascal Meschkat
Philipp Edelmann
Joana Heinzelmann
Alexey Pryalukhin
Rainer Bohle
Julia Heinzelbecker
Michael Stöckle
Kerstin Junker
Publication date: 01-11-2019
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 11/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-03035-6

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

MicroRNAs in tumor samples and urinary extracellular vesicles as a putative diagnostic tool for muscle-invasive bladder cancer

Abstract

Purpose

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 11/2019

Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning

Structured multi-disciplinary psychosocial care for cancer patients and the perceived quality of care from the patient perspective: a cluster-randomized trial

Eukaryotic translation initiation factor 6 overexpression plays a major role in the translational control of gallbladder cancer

Impact of 9q deletions on the classification of patients with acute myeloid leukemia

A three-platelet mRNA set: MAX, MTURN and HLA-B as biomarker for lung cancer

Risk analyses of N2 lymph-node metastases in patients with T1 non-small cell lung cancer: a multi-center real-world observational study in China

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page