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ASAP3 is a downstream target of HIF-1α and is critical for progression of lung adenocarcinoma

Authors Zhang P, Sun J, Kai J, Peng Y, Liu X, Zhou F, Wu J

Received 26 December 2018

Accepted for publication 8 May 2019

Published 17 July 2019 Volume 2019:12 Pages 5793—5803


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Ms Shreya Arora

Peer reviewer comments 2

Editor who approved publication: Dr Gaetano Romano

Pingping Zhang,1,2,* Junwei Sun,2,* Jindan Kai,2 Yi Peng,2 Xiyou Liu,2 Fuxiang Zhou,1 Jianping Wu2

1Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430079, People’s Republic of China; 2Department of Oncology, Hubei Cancer Hospital, Affiliated Hubei Cancer Hospital of Huazhong University of Science and Technology, Wuhan 430079, People’s Republic of China

*These authors contributed equally to this work

Background: ASAP3 was first identified as a protein that promotes cell proliferation in hepatocellular carcinoma and later reported to be an Arf6-specific Arf GTPase-activating protein that regulates cell migration associated with cancer cell invasion.
Materials and methods: Patients and tissue samples were from Hubei Cancer Hospital, human lung adenocarcinoma cell lines were obtained from the cell bank of the Chinese Academy of Science, nude mice (BALB/c nu/nu) were obtained from Shanghai SLAC Laboratory Animal Co. Ltd. Our methods contained immunohistochemistry, Western blotting, reverse-transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, stable transfection of lung adenocarcinoma cells, chromatin immunoprecipitation (CHIP) and luciferase assay, wound healing and cell migration assay.
Results: In this study, we show that ASAP3 overexpression promotes migration and invasiveness in human lung adenocarcinoma cells and accelerates tumor progression in a xenograft mouse model. In patient tumor samples, ASAP3 overexpression was significantly associated with lymph node metastasis and reduced overall survival. We also show that ASAP3 expression is induced under hypoxic conditions through hypoxia-inducible factor 1α (HIF-1α), which binds directly to HER1 or/and HER2 (hypoxia response element) in the ASAP3 promoter. ASAP3 overexpression counteracts the inhibition of lung adenocarcinoma progression caused by HIF-1α knockdown both in vitro and in vivo.
Conclusion: Our results identify ASAP3 as a downstream target of HIF-1α that is critical for metastatic progression in lung adenocarcinoma.

Keywords: lung adenocarcinoma, ASAP-3, hypoxia-inducible factor-1α, metastasis

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