CEBPD amplification and overexpression in urothelial carcinoma

A driver of tumor metastasis indicating adverse prognosis

Yu Hui Wang, Wen Jeng Wu, Wei Jan Wang, Hsuan Ying Huang, Wei Ming Li, Bi Wen Yeh, Ting Feng Wu, Yow Ling Shiue, Jim Jinn Chyuan Sheu, Ju-Ming Wang, Chien Feng Li

研究成果: Article

20 引文 (Scopus)

摘要

The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness.

原文English
頁(從 - 到)31069-31084
頁數16
期刊Oncotarget
6
發行號31
DOIs
出版狀態Published - 2015 一月 1

指紋

Neoplasm Metastasis
Carcinoma
Neoplasms
Laser Capture Microdissection
Nucleic Acid Hybridization
Polymerase Chain Reaction
Messenger RNA
Chromatin Immunoprecipitation
Urinary Tract
Oncogenes
Genetic Promoter Regions
Transcriptional Activation
Cell Movement
Down-Regulation
Immunohistochemistry
Cell Proliferation
Phenotype
Gene Expression
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

引用此文

Wang, Y. H., Wu, W. J., Wang, W. J., Huang, H. Y., Li, W. M., Yeh, B. W., ... Li, C. F. (2015). CEBPD amplification and overexpression in urothelial carcinoma: A driver of tumor metastasis indicating adverse prognosis. Oncotarget, 6(31), 31069-31084. https://doi.org/10.18632/oncotarget.5209
Wang, Yu Hui ; Wu, Wen Jeng ; Wang, Wei Jan ; Huang, Hsuan Ying ; Li, Wei Ming ; Yeh, Bi Wen ; Wu, Ting Feng ; Shiue, Yow Ling ; Sheu, Jim Jinn Chyuan ; Wang, Ju-Ming ; Li, Chien Feng. / CEBPD amplification and overexpression in urothelial carcinoma : A driver of tumor metastasis indicating adverse prognosis. 於: Oncotarget. 2015 ; 卷 6, 編號 31. 頁 31069-31084.
@article{6e95698e936c46eb9fac314c138339a8,
title = "CEBPD amplification and overexpression in urothelial carcinoma: A driver of tumor metastasis indicating adverse prognosis",
abstract = "The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8{\%}) and distal metastasis (50.0{\%}) but was barely detected in non-eventful cases (3.7{\%} and 0{\%}, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3{\%}) and overexpression (29.8{\%}) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness.",
author = "Wang, {Yu Hui} and Wu, {Wen Jeng} and Wang, {Wei Jan} and Huang, {Hsuan Ying} and Li, {Wei Ming} and Yeh, {Bi Wen} and Wu, {Ting Feng} and Shiue, {Yow Ling} and Sheu, {Jim Jinn Chyuan} and Ju-Ming Wang and Li, {Chien Feng}",
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month = "1",
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Wang, YH, Wu, WJ, Wang, WJ, Huang, HY, Li, WM, Yeh, BW, Wu, TF, Shiue, YL, Sheu, JJC, Wang, J-M & Li, CF 2015, 'CEBPD amplification and overexpression in urothelial carcinoma: A driver of tumor metastasis indicating adverse prognosis', Oncotarget, 卷 6, 編號 31, 頁 31069-31084. https://doi.org/10.18632/oncotarget.5209

CEBPD amplification and overexpression in urothelial carcinoma : A driver of tumor metastasis indicating adverse prognosis. / Wang, Yu Hui; Wu, Wen Jeng; Wang, Wei Jan; Huang, Hsuan Ying; Li, Wei Ming; Yeh, Bi Wen; Wu, Ting Feng; Shiue, Yow Ling; Sheu, Jim Jinn Chyuan; Wang, Ju-Ming; Li, Chien Feng.

於: Oncotarget, 卷 6, 編號 31, 01.01.2015, p. 31069-31084.

研究成果: Article

TY - JOUR

T1 - CEBPD amplification and overexpression in urothelial carcinoma

T2 - A driver of tumor metastasis indicating adverse prognosis

AU - Wang, Yu Hui

AU - Wu, Wen Jeng

AU - Wang, Wei Jan

AU - Huang, Hsuan Ying

AU - Li, Wei Ming

AU - Yeh, Bi Wen

AU - Wu, Ting Feng

AU - Shiue, Yow Ling

AU - Sheu, Jim Jinn Chyuan

AU - Wang, Ju-Ming

AU - Li, Chien Feng

PY - 2015/1/1

Y1 - 2015/1/1

N2 - The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness.

AB - The molecular aberrations responsible for the progression of urothelial carcinoma (UC) remain largely obscure. To search candidate driver oncogenes in UC, we performed array-based genomic hybridization (aCGH) on 40 UBUC samples. Amplification of 8q11.21 was preferentially identified in patients who developed disease-specific death (53.8%) and distal metastasis (50.0%) but was barely detected in non-eventful cases (3.7% and 0%, respectively). In order to quantify the expression of candidate genes harbored in 8q11.21, laser-capture microdissection coupled with RT-PCR was performed on 32 of the 40 cases submitted to aCGH. With this, we identified CEBPD mRNA expression as most significantly associated with gains of 8q11.21, suggesting amplification-driven expression. By performing CEBPD-specific FISH and immunohistochemistry on 295 UBUCs, we confirmed CEBPD amplification (21.3%) and overexpression (29.8%) were strongly related to each other (p<0.001). Moreover, both were associated with adverse clinicopathologic features and worse outcomes. Furthermore, the clinical significance of CEBPD expression was also confirmed in an independent cohort comprised of 340 UCs from the upper urinary tract. Interestingly, CEBPD knockdown suppressed cell proliferation, migration and, most significantly, cell invasion ability in UC cells. The latter phenotype is attributed to downregulation of MMP2 as identified by RT2 Profiler PCR array. Moreover, expression of CEBPD significantly enhanced MMP2 expression and transcriptional activation by directly binding to its promoter region, as confirmed by promoter reporter assay and chromatin immunoprecipitation assay. Conclusively, CEBPD amplification is a mechanism driving increased mRNA and protein expression that confers aggressiveness in UC through MMP2-mediated cell invasiveness.

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