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Gastric Cancer

, Volume 22, Issue 1, pp 91–103 | Cite as

FoxM1 is regulated by both HIF-1α and HIF-2α and contributes to gastrointestinal stromal tumor progression

  • Chenguang Bai
  • Xiaohong Liu
  • Cen Qiu
  • Jianming ZhengEmail author
Original Article
  • 232 Downloads

Abstract

Background

FoxM1 plays important regulatory roles in a variety of diseases. However, the functional role of FoxM1 and mechanisms responsible for its expression in gastrointestinal stromal tumor (GIST) is not thoroughly understood.

Methods

FoxM1 protein expression and biological function were examined in human GIST tissues and cells using immunohistochemistry, quantitative real-time PCR, western blot, CCK-8, wound-healing- and Matrigel invasion assays, respectively. The role of hypoxia-inducible factor (HIF) signaling in FoxM1 expression was investigated using chromatin immunoprecipitation and luciferase reporter and in vivo tumor growth assays.

Results

FoxM1 was highly expressed in highly proliferative and migratory/invasive GIST specimens. Upregulation of FoxM1 was positively correlated with the expression of HIF-1α and HIF-2α in GIST specimens, and hypoxia-induced FoxM1 expression in GIST cells. Functionally, ectopic expression of FoxM1 significantly promoted GIST cell proliferation, cell cycle progression, migration and invasion, whereas the knockdown of endogenous FoxM1 of hypoxic GIST cells had the opposite effects. Molecularly, FoxM1 was transcriptionally regulated by HIF-2α under normoxia, whereas it was upregulated by both HIF-1α and HIF-2α under hypoxia. The xenograft tumor data further confirmed the regulated effect of HIF-1α and HIF-2α on FoxM1, and demonstrated that the simultaneous downregulation of both HIF-1α and HIF-2α inhibited GIST tumor growth.

Conclusions

Our data demonstrated the critical role of FoxM1 in promoting GIST progression and uncovered a novel HIF-1α/HIF-2α-FoxM1 axis. These findings identify FoxM1 as a possible new molecular target for designing novel therapeutic treatments to control GIST progression.

Keywords

Gastrointestinal stromal tumor Progression FoxM1 HIF-1α HIF-2α 

Abbreviations

CdK2

Cyclin-dependent kinase 2

ChIP

Chromatin immunoprecipitation

GIST

Gastrointestinal stromal tumor

HIF

Hypoxia-inducible factor

HRE

Hypoxia response element

MMP-2

Matrix metalloproteinase-2

PDGFRA

Platelet-derived growth factor receptor alpha

PCNA

Proliferating cell nuclear antigen

PBS

Phosphate-buffered saline

PT

PT-2385

PX

PX-478 2HCl

qPCR

Quantitative polymerase chain reaction

SD

Standard error

shRNA

Short hairpin RNA

Notes

Acknowledgements

This work was supported by National Natural Science Foundation of China (Grants 81472276) and Shanghai Municipal Commission of Health and Family planning, Key Developing Disciplines (No. 2015ZB0202).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients for the use of their samples.

Supplementary material

10120_2018_846_MOESM1_ESM.docx (6.7 mb)
Supplementary material 1 (DOCX 6879 KB)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Chenguang Bai
    • 1
  • Xiaohong Liu
    • 1
  • Cen Qiu
    • 1
  • Jianming Zheng
    • 1
    Email author
  1. 1.Department of Pathology, Changhai HospitalSecond Military Medical UniversityShanghaiChina

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