单位：[1]Henan Key Laboratory of immunology and targeted therapy, School ofLaboratory Medicine, Henan Collaborative Innovation Center of MolecularDiagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, Henan Province, People’s Republic of China[2]Department ofGastroenterology, The Third Affiliated Hospital of Xinxiang Medical University,Xinxiang, Henan, China[3]Phil Rivers Technology (Beijing) Ltd, Beijing, China[4]Department of Cancer genomics, LemonData biotech (Shenzhen) Ltd,Shenzhen, China深圳市康宁医院深圳医学信息中心[5]Department of Medical Oncology, Peking UniversityInternational Hospital, Beijing, China[6]Department of General Surgery, BeijingFriendship Hospital, Capital Medical University, National Clinical ResearchCenter of Digestive Diseases, Beijing Key Laboratory of Cancer Invasion andMetastasis Research & National Clinical Research Center of Digestive Diseases,Beijing 100050, China临床科室国家中心普外分中心普外五科（综合普外科）首都医科大学附属北京友谊医院[7]Department of Physiology, University of TexasSouthwestern Medical Center, Dallas, TX 75390, USA[8]Key Laboratory ofCarcinogenesis and Translational Research (Ministry of Education)Department of Renal cancer and Melanoma, Peking University School ofOncology, Beijing Cancer Hospital and Institute, Beijing, China[9]Center forCancer Research, Xinxiang Medical University, Xinxiang, Henan, China[10]Department of Molecular Biology, University of Texas SouthwesternMedical Center, Dallas, TX 75390, USA[11]Xinxiang Medical University, Schoolof Laboratory Medicine, Xinxiang, Henan Province, China
Background: Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy. Methods: SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha. Results: Here, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48-specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment. Conclusions: Our study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast cancer treatment.
基金：
National Science Foundation for Young Scientists of China [8170110153]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [U1604190]; Program for Innovative Research Team (in Science and Technology) in University of Henan Province [15IRTSTHN025]; National High Technology Research and Development Program of ChinaNational High Technology Research and Development Program of China [2012AA02A201-1]; Foundation of Henan Educational Committee [16A310014, 17A310025]; Xinxiang Medical University; graduate innovative practice base for clinical medicine of Xinxiang Medical University, Yashijie medical laboratory institute, School of laboratory medicine, Xinxiang Medical University
第一作者单位：[1]Henan Key Laboratory of immunology and targeted therapy, School ofLaboratory Medicine, Henan Collaborative Innovation Center of MolecularDiagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, Henan Province, People’s Republic of China
共同第一作者：
通讯作者：
通讯机构：[1]Henan Key Laboratory of immunology and targeted therapy, School ofLaboratory Medicine, Henan Collaborative Innovation Center of MolecularDiagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, Henan Province, People’s Republic of China[3]Phil Rivers Technology (Beijing) Ltd, Beijing, China[4]Department of Cancer genomics, LemonData biotech (Shenzhen) Ltd,Shenzhen, China[10]Department of Molecular Biology, University of Texas SouthwesternMedical Center, Dallas, TX 75390, USA[11]Xinxiang Medical University, Schoolof Laboratory Medicine, Xinxiang, Henan Province, China
推荐引用方式(GB/T 7714)：
Yang Huijie,Yu Na,Xu Juntao,et al.SMURF1 facilitates estrogen receptor. signaling in breast cancer cells[J].JOURNAL of EXPERIMENTAL & CLINICAL CANCER RESEARCH.2018,37:doi:10.1186/s13046-018-0672-z.
APA：
Yang, Huijie,Yu, Na,Xu, Juntao,Ding, Xiaosheng,Deng, Wei...&Zhuang, Ting.(2018).SMURF1 facilitates estrogen receptor. signaling in breast cancer cells.JOURNAL of EXPERIMENTAL & CLINICAL CANCER RESEARCH,37,
MLA：
Yang, Huijie,et al."SMURF1 facilitates estrogen receptor. signaling in breast cancer cells".JOURNAL of EXPERIMENTAL & CLINICAL CANCER RESEARCH 37.(2018)
医学