Oncotarget

Research Papers:

Insulin growth factor binding protein 2 mediates the progression of lymphangioleiomyomatosis

Xiangke Li, Xiaolei Liu, Linda Zhang, Chenggang Li, Erik Zhang, Wang Ma, Qingxia Fan _ and Jane J. Yu

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Oncotarget. 2017; 8:36628-36638. https://doi.org/10.18632/oncotarget.16695

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Abstract

Xiangke Li1,2,*, Xiaolei Liu2,*, Linda Zhang3, Chenggang Li2, Erik Zhang2, Wang Ma1, Qingxia Fan1 and Jane J. Yu1,2

1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Zhengzhou 450052, China

2Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA

3Program in Behavioral Neuroscience, Northeastern University, Boston, MA 02115, USA

*These authors have contributed equally to this work

Correspondence to:

Qingxia Fan, email: fqx2243@126.com

Jane J. Yu, email: jane.yu@uc.edu

Keywords: IGFBP2, estrogen, lymphangioleiomyomatosis, ERα, nuclear localization

Received: February 10, 2017    Accepted: March 15, 2017    Published: March 30, 2017

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease that almost exclusively affects women. LAM cells migrate to the lungs, where they cause cystic destruction of lung parenchyma. Mutations in TSC1 or TSC2 lead to the activation of the mammalian target of rapamycin complex-1, a kinase that regulates growth factor-dependent protein translation, cell growth, and metabolism. Insulin-like growth factor binding protein 2 (IGFBP2) binds insulin, IGF1 and IGF2 in circulation, thereby modulating cell survival, migration, and invasion in neoplasms. In this study, we identified that IGFBP2 primarily localized in the nucleus of TSC2-null LAM patient-derived cells in vitro and in vivo. We also showed that nuclear accumulation of IGFBP2 is closely associated with estrogen receptor alpha (ERa) expression. Furthermore, estrogen treatment induced IGFBP2 nuclear translocation in TSC2-null LAM patient-derived cells. Importantly, depletion of IGFBP2 by siRNA reduced cell proliferation, enhanced apoptosis, and decreased migration and invasion of TSC2-null LAM patient-derived cells. More interestingly, depletion of IGFBP2 markedly decreased the phosphorylation of MAPK in LAM patient-derived TSC2-null cells. Collectively, these results suggest that IGFBP2 plays an important role in promoting tumorigenesis, through estrogen and ERalpha signaling pathway. Thus, targeting IGFBP2 may serve as a potential therapeutic strategy for women with LAM and other female gender specific neoplasms.


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