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

Abstract

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.