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Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth

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Abstract

Background

Adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome, called Cushing disease, is caused by a corticotroph tumor of the pituitary gland. Insulin-like growth factor binding protein 6 (IGFBP6), which regulates insulin-like growth factor (IGF) activity and inhibits several IGF2-dependent cancer growths, plays a pivotal role in the tumorigenesis of malignancy, but its roles in ACTH-secreting pituitary adenomas remain unclear.

Objective

To investigate IGFBP6 expression in ACTH-secreting pituitary adenomas, and its involvement in tumor growth.

Methods

Sporadic ACTH-secreting pituitary adenomas specimens (n = 41) and adjacent non-tumorous pituitary tissues (n = 9) were collected by transphenoidal surgery. IGFBP6 expression was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and validated by Western blotting. Associations of IGFBP6 expression with maximum tumor diameter or Ki-67 labeling index were evaluated in ACTH-secreting pituitary adenomas.

Results

IGFBP6 mRNA and protein expression were both decreased in ACTH-secreting pituitary adenomas, compared to adjacent non-tumorous pituitary tissues (P < 0.01). IGFBP6 expression was correlated inversely with maximum tumor diameter (Rho = −0.53, P < 0.0001) and Ki-67 levels (Rho = −0.52, P < 0.05). Moreover, IGFBP6 downregulation activated PI3 K-AKT-mTOR pathway in ACTH-secreting pituitary adenomas.

Conclusions

IGFBP6 attenuation in ACTH-secreting pituitary adenomas is associated with tumor growth, through activation of PI3K-AKT-mTOR pathway. The finding underlies IGFBP6 roles in Cushing disease and would potentially provide a novel target of medical therapies.

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Acknowledgments

Authors thank Dr. Cuiqi Zhou (Cedars-Sinai Medical Center, Los Angeles, California) for helpful discussion and editing of this manuscript. This work is supported by National Natural Science Foundation of China (Grant 81072084), the Ministry of Science and Technology of China (2011AA020112 and 2014BAI04B00).

Conflict of interest

The authors do not have conflict of interests.

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Authors and Affiliations

  1. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China

    Yakun Yang, Xiaohai Liu, Yong Yao, Congxin Dai, Bowen Sun, Yonghui Jiao, Zhenqing Wei & Renzhi Wang

  2. State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing, 100005, China

    Miaomiao Sheng, Fengming Huang, Jindong Zhu & Chengyu Jiang

  3. Bioinformatics Research Group, Advanced Computing Research Laboratory, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100190, China

    Dechao Bu & Yi Zhao

  4. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China

    Huijuan Zhu & Lin Lu

  5. Center for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China

    Chengyu Jiang

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  1. Yakun Yang
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  2. Miaomiao Sheng
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Corresponding authors

Correspondence to Chengyu Jiang or Renzhi Wang.

Additional information

Yakun Yang and Miaomiao Sheng have contributed equally to this work.

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Yang, Y., Sheng, M., Huang, F. et al. Downregulation of Insulin-like growth factor binding protein 6 is associated with ACTH-secreting pituitary adenoma growth. Pituitary 17, 505–513 (2014). https://doi.org/10.1007/s11102-013-0535-8

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  • DOI: https://doi.org/10.1007/s11102-013-0535-8

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