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Oncogene volume 38, pages 6338–6353 (2019)
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High circulating insulin-like growth factor-1 (IGF-1) levels increase the risk of prostate cancer. However, whether circulating IGF-1 levels directly aggravate prostate cancer remains elusive. In this study, we crossed a transgenic prostate adenocarcinoma mouse model, Hi-Myc mice, with a liver-specific IGF-1 transgenic mouse model (HIT) to increase their circulating IGF-1 levels to investigate the impact of the elevated circulating IGF-1 on prostate cancer development in vivo. The Hi-Myc/HIT mice had increased incidence and invasiveness of prostate cancer. IGF-1 elevation led to the accumulation of FOXO3A in the cytosol of prostate tumor cells and downregulation of its target gene Bim, which resulted in the apoptosis inhibition and prostate cancer overgrowth. The differential expressions of IGF-1R, FOXO3A, and BIM in the benign versus malignant prostate tissues supported a negative association between the FOXO3A/BIM axis and IGF-1R expression in human prostate adenocarcinoma. Our findings suggest that targeting the IGF-1/FOXO3A/BIM signaling axis could be an attractive strategy for prostate cancer prevention or treatment.
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This study was supported by the Nature Science Foundation of China (NSFC) No. 81471000, No. 31871163, and Ministry of Science and Technology (No. 2014DFA32120) to Yingjie Wu.
These authors contributed equally: Shuang Wang, Ning Wang
Institute of Genome Engineered Animal Models for Human Diseases, Dalian Medical University, Dalian, Liaoning, 116044, China
Shuang Wang, Ning Wang, Bin Yu, Mingxing Cao, Li Zeng & Yingjie Wu
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, 116044, China
Shuang Wang, Ning Wang, Bin Yu, Mingxing Cao, Li Zeng & Yingjie Wu
College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China
Shuang Wang, Ning Wang & Yingjie Wu
College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, Heilongjiang, 157011, China
Mingxing Cao
Department of Urology Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, 116033, China
Yanlong Wang
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA
Yuqi Guo, Yanli Zhang, Xin Li & Yingjie Wu
Department of Endocrinology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116027, China
Ping Zhang
Department of Pathology, Dalian Medical University, Dalian, Liaoning, 116044, China
Xiao Yu
Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning, 116044, China
Shujing Wang
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, CAS Center for Excellence in Animal Evolution and Genetics, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
Bin Liang
Department of Urology, New York University Langone Medical Center, New York, NY, 10016, USA
Xin Li
Perlmutter Cancer Institute, New York University Langone Medical Center, New York, NY, 10016, USA
Xin Li
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York, NY, 10029, USA
Yingjie Wu
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Correspondence to Bin Liang, Xin Li or Yingjie Wu.
The authors declare that they have no conflict of interest.
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Wang, S., Wang, N., Yu, B. et al. Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model. Oncogene 38, 6338–6353 (2019). https://doi.org/10.1038/s41388-019-0880-9
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DOI: https://doi.org/10.1038/s41388-019-0880-9
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