Testicular orphan nuclear receptor 4-associated protein 16 promotes non-small cell lung carcinoma by activating estrogen receptor β and blocking testicular orphan nuclear receptor 2

Fang,Fang; Zheng,Qingfeng; Zhang,Jianzhi; Dong,Bin; Zhu,Sainan; Huang,Xiaoyun; Wang,Yang; Zhao,Bingtian; Li,Shaolei; Xiong,Hongchao; Chen,Jinfeng; Wu,Nan; Song,Sonya  Wei; Chang,Chawnshang; Yang,Yue

doi:10.3892/or.2012.2107

Testicular orphan nuclear receptor 4-associated protein 16 promotes non-small cell lung carcinoma by activating estrogen receptor β and blocking testicular orphan nuclear receptor 2

Authors:
- Fang Fang
- Qingfeng Zheng
- Jianzhi Zhang
- Bin Dong
- Sainan Zhu
- Xiaoyun Huang
- Yang Wang
- Bingtian Zhao
- Shaolei Li
- Hongchao Xiong
- Jinfeng Chen
- Nan Wu
- Sonya Wei Song
- Chawnshang Chang
- Yue Yang
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Affiliations: Department of Thoracic Surgery Ⅱ, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Department of Medical Statistics, Peking University First Hospital, Beijing 100034, P.R. China, Department of Clinical Research Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Departments of Pathology, Urology, Radiation Oncology, and Cancer Center, George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY 14642, USA
Published online on: October 26, 2012 https://doi.org/10.3892/or.2012.2107
Pages: 297-305

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Abstract

The possible involvement of estrogen receptors (ERs) and testicular orphan nuclear receptors (TRs) in human non-small cell lung carcinoma (NSCLC) has been suggested, but their precise roles and their relationship remain largely unknown. This study aimed to investigate whether TR4-associated protein 16 (TRA16) regulates the ERβ and TR2 pathways and could be a potential target in NSCLC. We used tissue microarrays including NSCLC tissues (n=154) and negative controls (n=14) to examine the expression of TRA16 and ERβ, and in vitro reporter gene assays, the mammalian two-hybrid method and immunoprecipitation in Cos-1 cells to investigate the relationships among TRA16, ERβ and TR2. We found that TRA16 was highly expressed in approximately 90% of the NSCLC tissues examined. TRA16 overexpression was significantly associated with TNM stage, tumor size, lymph node metastasis, tumor thrombus in vein, tumor differentiation and prognosis of NSCLC patients, in which TRA16 was shown to be an independent prognostic factor. Introduction of TRA16 into Cos-1 cells enhanced cell proliferation. Co-expression of TRA16 and ERβ in Cos-1 cells using different reporter gene systems and mammalian two-hybrid approaches revealed that TRA16 enhanced ERβ-mediated transcriptional activity. By adopting similar approaches, and immunoprecipitation and immunocytofluorescence assays, we found that TRA16 also interacted with TR2, and blocked the TR2 inhibitory effect on ERβ. Our findings demonstrate that TRA16 could be a promising diagnostic and prognostic biomarker in NSCLC, and promotes cancer cell growth through activation of the ERβ pathway by interacting with ERβ and TR2.

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