Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model

Shuang Wang; Ning Wang; Bin Yu; Mingxing Cao; Yanlong Wang; Yuqi Guo; Yanli Zhang; Ping Zhang; Xiao Yu; Shujing Wang; Li Zeng; Bin Liang; Xin Li; Yingjie Wu

doi:10.1038/s41388-019-0880-9

Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model

Oncogene. 2019 Sep;38(36):6338-6353. doi: 10.1038/s41388-019-0880-9. Epub 2019 Jul 16.

Authors

Shuang Wang^{1

2

3}, Ning Wang^{1

2

3}, Bin Yu^{1

2}, Mingxing Cao^{1

2

4}, Yanlong Wang⁵, Yuqi Guo⁶, Yanli Zhang⁶, Ping Zhang⁷, Xiao Yu⁸, Shujing Wang⁹, Li Zeng^{1

2}, Bin Liang¹⁰, Xin Li^{11

12

13}, Yingjie Wu^{14

15

16

17

18}

Affiliations

¹ Institute of Genome Engineered Animal Models for Human Diseases, Dalian Medical University, Dalian, Liaoning, 116044, China.
² National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, 116044, China.
³ College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China.
⁴ College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, Heilongjiang, 157011, China.
⁵ Department of Urology Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, 116033, China.
⁶ Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA.
⁷ Department of Endocrinology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116027, China.
⁸ Department of Pathology, Dalian Medical University, Dalian, Liaoning, 116044, China.
⁹ Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning, 116044, China.
¹⁰ 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. liangb@mail.kiz.ac.cn.
¹¹ Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA. xl15@nyu.edu.
¹² Department of Urology, New York University Langone Medical Center, New York, NY, 10016, USA. xl15@nyu.edu.
¹³ Perlmutter Cancer Institute, New York University Langone Medical Center, New York, NY, 10016, USA. xl15@nyu.edu.
¹⁴ Institute of Genome Engineered Animal Models for Human Diseases, Dalian Medical University, Dalian, Liaoning, 116044, China. yingjiewu@dmu.edu.cn.
¹⁵ National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, 116044, China. yingjiewu@dmu.edu.cn.
¹⁶ College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China. yingjiewu@dmu.edu.cn.
¹⁷ Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA. yingjiewu@dmu.edu.cn.
¹⁸ Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York, NY, 10029, USA. yingjiewu@dmu.edu.cn.

PMID: 31312023
DOI: 10.1038/s41388-019-0880-9

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma* / blood
Adenocarcinoma* / genetics
Adenocarcinoma* / pathology
Animals
Bcl-2-Like Protein 11 / genetics
Bcl-2-Like Protein 11 / physiology*
Cell Line, Tumor
Cohort Studies
Disease Models, Animal
Disease Progression
Forkhead Box Protein O3 / genetics
Forkhead Box Protein O3 / physiology*
Gene Expression Regulation, Neoplastic
Humans
Insulin-Like Growth Factor I / metabolism
Insulin-Like Growth Factor I / physiology*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
PC-3 Cells
Prostatic Neoplasms* / blood
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology
Signal Transduction / genetics

Substances

Bcl-2-Like Protein 11
FOXO3 protein, human
Forkhead Box Protein O3
FoxO3 protein, mouse
IGF1 protein, human
insulin-like growth factor-1, mouse
Insulin-Like Growth Factor I