Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer

Erik D Wiklund; Jesper B Bramsen; Toby Hulf; Lars Dyrskjøt Andersen; Ramshanker Ramanathan; Thomas B Hansen; Sune B Villadsen; Shan Gao; Marie S Ostenfeld; Michael Borre; Marcus E Peter; Torben F Ørntoft; Jørgen Kjems; Susan J Clark

doi:10.1002/ijc.25461

Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer

Erik D Wiklund, Jesper B Bramsen, Toby Hulf, Lars Dyrskjøt Andersen, Ramshanker Ramanathan, Thomas B Hansen, Sune B Villadsen, Shan Gao, Marie S Ostenfeld, Michael Borre, Marcus E Peter, Torben F Ørntoft, Jørgen Kjems, Susan J Clark

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

335 Citations (Scopus)

Abstract

MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

Translated title of the contribution	Koordineret epigenetisk repression af miR-200 familien og miR-205 i invasiv blærecancer
Original language	English
Journal	International Journal of Cancer
Volume	128
Issue	6
Pages (from-to)	1327-1334
Number of pages	8
ISSN	0020-7136
DOIs	https://doi.org/10.1002/ijc.25461
Publication status	Published - 15 Mar 2011

Keywords

Cells, Cultured
DNA Methylation
Epigenomics
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs
Neoplasm Invasiveness
Polymerase Chain Reaction
Urinary Bladder
Urinary Bladder Neoplasms

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Cite this

Wiklund, E. D., Bramsen, J. B., Hulf, T., Andersen, L. D., Ramanathan, R., Hansen, T. B., Villadsen, S. B., Gao, S., Ostenfeld, M. S., Borre, M., Peter, M. E., Ørntoft, T. F., Kjems, J., & Clark, S. J. (2011). Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. International Journal of Cancer, 128(6), 1327-1334. https://doi.org/10.1002/ijc.25461

@article{217ecec62d4e4a68b74e26f6c528d976,

title = "Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer",

abstract = "MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.",

keywords = "Cells, Cultured, DNA Methylation, Epigenomics, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Neoplasm Invasiveness, Polymerase Chain Reaction, Urinary Bladder, Urinary Bladder Neoplasms",

author = "Wiklund, {Erik D} and Bramsen, {Jesper B} and Toby Hulf and Andersen, {Lars Dyrskj{\o}t} and Ramshanker Ramanathan and Hansen, {Thomas B} and Villadsen, {Sune B} and Shan Gao and Ostenfeld, {Marie S} and Michael Borre and Peter, {Marcus E} and {\O}rntoft, {Torben F} and J{\o}rgen Kjems and Clark, {Susan J}",

note = "Copyright {\textcopyright} 2010 UICC.",

year = "2011",

month = mar,

day = "15",

doi = "10.1002/ijc.25461",

language = "English",

volume = "128",

pages = "1327--1334",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Blackwell",

number = "6",

}

Wiklund, ED, Bramsen, JB, Hulf, T, Andersen, LD, Ramanathan, R, Hansen, TB, Villadsen, SB, Gao, S, Ostenfeld, MS, Borre, M, Peter, ME, Ørntoft, TF , Kjems, J & Clark, SJ 2011, 'Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer', International Journal of Cancer, vol. 128, no. 6, pp. 1327-1334. https://doi.org/10.1002/ijc.25461

Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. / Wiklund, Erik D; Bramsen, Jesper B; Hulf, Toby et al.
In: International Journal of Cancer, Vol. 128, No. 6, 15.03.2011, p. 1327-1334.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer

AU - Wiklund, Erik D

AU - Bramsen, Jesper B

AU - Hulf, Toby

AU - Andersen, Lars Dyrskjøt

AU - Ramanathan, Ramshanker

AU - Hansen, Thomas B

AU - Villadsen, Sune B

AU - Gao, Shan

AU - Ostenfeld, Marie S

AU - Borre, Michael

AU - Peter, Marcus E

AU - Ørntoft, Torben F

AU - Kjems, Jørgen

AU - Clark, Susan J

PY - 2011/3/15

Y1 - 2011/3/15

N2 - MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

AB - MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

KW - Cells, Cultured

KW - DNA Methylation

KW - Epigenomics

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - MicroRNAs

KW - Neoplasm Invasiveness

KW - Polymerase Chain Reaction

KW - Urinary Bladder

KW - Urinary Bladder Neoplasms

U2 - 10.1002/ijc.25461

DO - 10.1002/ijc.25461

M3 - Journal article

C2 - 20473948

SN - 0020-7136

VL - 128

SP - 1327

EP - 1334

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 6

ER -