Research Papers:

The cAMP responsive element binding protein 1 transactivates epithelial membrane protein 2, a potential tumor suppressor in the urinary bladder urothelial carcinoma

Chien-Feng Li _, Wen-Jeng Wu, Wen-Ren Wu, Yu-Jing Liao, Lih-Ren Chen, Chun-Nung Huang, Ching-Chia Li, Wei-Ming Li, Hsuan-Ying Huang, Yi-Ling Chen, Shih-Shin Liang, Nan-Haw Chow and Yow-Ling Shiue

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Oncotarget. 2015; 6:9220-9239. https://doi.org/10.18632/oncotarget.3312

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Chien-Feng Li1,2,3,*, Wen-Jeng Wu4,5,6,7,*, Wen-Ren Wu8, Yu-Jing Liao9, Lih-Ren Chen3,9, Chun-Nung Huang6,7,8, Ching-Chia Li6,7,10, Wei-Ming Li4,5,7,11, Hsuan-Ying Huang12, Yi-Ling Chen8, Shih-Shin Liang8,13, Nan-Haw Chow14,15, Yow-Ling Shiue8,16,17

1Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

2National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

3Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

4Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

6Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

7Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan

8Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan

9Division of Physiology, Livestock Research Institute, Tainan, Taiwan

10Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

11Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan

12Department of Pathology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

13Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan

14Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan

15Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan

16Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan

17Doctoral degree program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Yow-Ling Shiue, e-mail: [email protected]

Keywords: EMP2, CREB1, urinary bladder urothelial carcinoma, tumor suppressor

Received: October 20, 2014     Accepted: February 08, 2015     Published: April 13, 2015


In this study, we report that EMP2 plays a tumor suppressor role by inducing G2/M cell cycle arrest, suppressing cell viability, proliferation, colony formation/anchorage-independent cell growth via regulation of G2/M checkpoints in distinct urinary bladder urothelial carcinoma (UBUC)-derived cell lines. Genistein treatment or exogenous expression of the cAMP responsive element binding protein 1 (CREB1) gene in different UBUC-derived cell lines induced EMP2 transcription and subsequent translation. Mutagenesis on either or both cAMP-responsive element(s) dramatically decreased the EMP2 promoter activity with, without genistein treatment or exogenous CREB1 expression, respectively. Significantly correlation between the EMP2 immunointensity and primary tumor, nodal status, histological grade, vascular invasion and mitotic activity was identified. Multivariate analysis further demonstrated that low EMP2 immunoexpression is an independent prognostic factor for poor disease-specific survival. Genistein treatments, knockdown of EMP2 gene and double knockdown of CREB1 and EMP2 genes significantly inhibited tumor growth and notably downregulated CREB1 and EMP2 protein levels in the mice xenograft models. Therefore, genistein induced CREB1 transcription, translation and upregulated pCREB1(S133) protein level. Afterward, pCREB1(S133) transactivated the tumor suppressor gene, EMP2, in vitro and in vivo. Our study identified a novel transcriptional target, which plays a tumor suppressor role, of CREB1.

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