Hypoxia‑inducible factor 1 mediates intermittent hypoxia‑induced migration of human breast cancer MDA‑MB‑231 cells

Liu,Litao; Liu,Wenlan; Wang,Lili; Zhu,Ting; Zhong,Jianhua; Xie,Ni

doi:10.3892/ol.2017.7223

Hypoxia‑inducible factor 1 mediates intermittent hypoxia‑induced migration of human breast cancer MDA‑MB‑231 cells

Authors:
- Litao Liu
- Wenlan Liu
- Lili Wang
- Ting Zhu
- Jianhua Zhong
- Ni Xie
View Affiliations

Affiliations: The Central Laboratory, Shenzhen Second People's Hospital, Shenzhen University First Affiliated Hospital, Shenzhen, Guangdong 518035, P.R. China
Published online on: October 19, 2017 https://doi.org/10.3892/ol.2017.7223
Pages: 7715-7722
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metastasis is the major cause of triple‑negative breast cancer (TNBC)‑associated mortality. Hypoxia promotes cancer cell migration and remote metastasis, which occur with hypoxia inducible factor 1α (HIF‑1α) stabilization and vimentin upregulation. However, the evolutionary dynamics that link the changes in HIF‑1α and vimentin levels under hypoxic conditions are not well understood. In the present study, the effects of intermittent hypoxia (IH), continuous hypoxia (CH) and normoxia on the migration and proliferation of human TNBC MDA‑MB‑231 cells were investigated. The results demonstrated that IH significantly increased the migration of MDA‑MB‑231 cells, and this effect was dependent on the number of cycles of hypoxia‑reoxygenation. Unexpectedly, IH significantly inhibited cell proliferation, while CH only caused such an effect if hypoxia extended for ≥3 days. IH and CH induced HIF‑1α protein accumulation and vimentin upregulation, with a greater effect observed in IH. Knockdown of HIF‑1α with siRNA abolished IH‑induced cell migration and vimentin upregulation. In summary, multiple cycles of hypoxia and reoxygenation have a more pronounced effect on the promotion of TNBC invasiveness than CH; HIF‑1α activation and downstream vimentin upregulation may account for this phenotypic change.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Papa A, Caruso D, Tomao S, Rossi L, Zaccarelli E and Tomao F: Triple-negative breast cancer: Investigating potential molecular therapeutic target. Expert Opin Ther Targets. 19:55–75. 2015. View Article : Google Scholar : PubMed/NCBI
3	Surazynski A, Miltyk W, Prokop I and Palka J: The effect of estrogen on prolidase-dependent regulation of HIF-1α expression in breast cancer cells. Mol Cell Biochem. 379:29–36. 2013. View Article : Google Scholar : PubMed/NCBI
4	National Cancer Institute, . SEER fact sheet for breast cancer. http://seer.cancer.gov/statfacts/html/breast.html.2005-2011
5	Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI
6	Tsai YP and Wu KJ: Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci. 19:1022012. View Article : Google Scholar : PubMed/NCBI
7	Liu ZJ, Semenza GL and Zhang HF: Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B. 16:32–43. 2015. View Article : Google Scholar : PubMed/NCBI
8	Agani F and Jiang BH: Oxygen-independent regulation of HIF-1: Novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets. 13:245–251. 2013. View Article : Google Scholar : PubMed/NCBI
9	Du J, Sun B, Zhao X, Gu Q, Dong X, Mo J, Sun T, Wang J, Sun R and Liu Y: Hypoxia promotes vasculogenic mimicry formation by inducing epithelial-mesenchymal transition in ovarian carcinoma. Gynecol Oncol. 133:575–583. 2014. View Article : Google Scholar : PubMed/NCBI
10	He G, Jiang Y, Zhang B and Wu G: The effect of HIF-1α on glucose metabolism, growth and apoptosis of pancreatic cancerous cells. Asia Pac J Clin Nutr. 23:174–180. 2014.PubMed/NCBI
11	Lei J, Fan L, Wei G, Chen X, Duan W, Xu Q, Sheng W, Wang K and Li X: Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer. Tumour Biol. 36:3119–3126. 2015. View Article : Google Scholar : PubMed/NCBI
12	Dave JM and Bayless KJ: Vimentin as an integral regulator of cell adhesion and endothelial sprouting. Microcirculation. 21:333–344. 2014. View Article : Google Scholar : PubMed/NCBI
13	Chernoivanenko IS and Minin AA and Minin AA: Role of vimentin in cell migration. Ontogenez. 44:186–202. 2013.(In Russian). PubMed/NCBI
14	Brown JM: Tumor hypoxia, drug resistance, and metastases. J Natl Cancer Inst. 82:338–339. 1990. View Article : Google Scholar : PubMed/NCBI
15	Helmlinger G, Yuan F, Dellian M and Jain RK: Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat Med. 3:177–182. 1997. View Article : Google Scholar : PubMed/NCBI
16	Liu Y, Song X, Wang X, Wei L, Liu X, Yuan S and Lv L: Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells. J Cell Biochem. 111:554–563. 2010. View Article : Google Scholar : PubMed/NCBI
17	Verduzco D, Lloyd M, Xu L, Ibrahim-Hashim A, Balagurunathan Y, Gatenby RA and Gillies RJ: Intermittent hypoxia selects for genotypes and phenotypes that increase survival, invasion, and therapy resistance. PLoS One. 10:e1209582015. View Article : Google Scholar
18	Bhaskara VK, Mohanam I, Rao JS and Mohanam S: Intermittent hypoxia regulates stem-like characteristics and differentiation of neuroblastoma cells. PLoS One. 7:e309052012. View Article : Google Scholar : PubMed/NCBI
19	Choi H, Gillespie DL, Berg S, Rice C, Couldwell S, Gu J, Colman H, Jensen RL and Huang LE: Intermittent induction of HIF-1α produces lasting effects on malignant progression independent of its continued expression. PLoS One. 10:e1251252015.
20	Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S and Kaelin WG Jr: Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1:222–235. 2011. View Article : Google Scholar : PubMed/NCBI
21	Miao ZF, Zhao TT, Wang ZN, Xu YY, Mao XY, Wu JH, Liu XY, Xu H, You Y and Xu HM: Influence of different hypoxia models on metastatic potential of SGC-7901 gastric cancer cells. Tumour Biol. 35:6801–6808. 2014. View Article : Google Scholar : PubMed/NCBI
22	Shi J, Wan Y and Di W: Effect of hypoxia and re-oxygenation on cell invasion and adhesion in human ovarian carcinoma cells. Oncol Rep. 20:803–807. 2008.PubMed/NCBI
23	Zhou W, Wang G, Zhao X, Xiong F, Zhou S, Peng J, Cheng Y, Xu S and Xu X: A multiplex qPCR gene dosage assay for rapid genotyping and large-scale population screening for deletional α-thalassemia. J Mol Diagn. 15:642–651. 2013. View Article : Google Scholar : PubMed/NCBI
24	Zhu H, Wang D, Zhang L, Xie X, Wu Y, Liu Y, Shao G and Su Z: Upregulation of autophagy by hypoxia-inducible factor-1α promotes EMT and metastatic ability of CD133+ pancreatic cancer stem-like cells during intermittent hypoxia. Oncol Rep. 32:935–942. 2014. View Article : Google Scholar : PubMed/NCBI
25	Almendros I, Wang Y and Gozal D: The polymorphic and contradictory aspects of intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 307:L129–L140. 2014. View Article : Google Scholar : PubMed/NCBI
26	Pires IM, Bencokova Z, Milani M, Folkes LK, Li JL, Stratford MR, Harris AL and Hammond EM: Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. Cancer Res. 70:925–935. 2010. View Article : Google Scholar : PubMed/NCBI
27	Zepeda AB, Pessoa A Jr, Castillo RL, Figueroa CA, Pulgar VM and Farías JG: Cellular and molecular mechanisms in the hypoxic tissue: Role of HIF-1 and ROS. Cell Biochem Funct. 31:451–459. 2013. View Article : Google Scholar : PubMed/NCBI
28	Noh MY, Kim YS, Lee KY, Lee YJ, Kim SH, Yu HJ and Koh SH: The early activation of PI3K strongly enhances the resistance of cortical neurons to hypoxic injury via the activation of downstream targets of the PI3K pathway and the normalization of the levels of PARP activity, ATP, and NAD+. Mol Neurobiol. 47:757–769. 2013. View Article : Google Scholar : PubMed/NCBI
29	Chen PY, Ho YR, Wu MJ, Huang SP, Chen PK, Tai MH, Ho CT and Yen JH: Cytoprotective effects of fisetin against hypoxia-induced cell death in PC12 cells. Food Funct. 6:287–296. 2015. View Article : Google Scholar : PubMed/NCBI
30	Toffoli S, Feron O, Raes M and Michiels C: Intermittent hypoxia changes HIF-1alpha phosphorylation pattern in endothelial cells: Unravelling of a new PKA-dependent regulation of HIF-1alpha. Biochim Biophys Acta. 1773:1558–1571. 2007. View Article : Google Scholar : PubMed/NCBI
31	Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M and Michiels C: Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem. 278:31277–31285. 2003. View Article : Google Scholar : PubMed/NCBI
32	Lee JW, Bae SH, Jeong JW, Kim SH and Kim KW: Hypoxia-inducible factor (HIF-1)alpha: Its protein stability and biological functions. Exp Mol Med. 36:1–12. 2004. View Article : Google Scholar : PubMed/NCBI
33	Monti E and Gariboldi MB: HIF-1 as a target for cancer chemotherapy, chemosensitization and chemoprevention. Curr Mol Pharmacol. 4:62–77. 2011. View Article : Google Scholar : PubMed/NCBI
34	Dewhirst MW: Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res. 67:854–855. 2007. View Article : Google Scholar : PubMed/NCBI
35	Moeller BJ, Cao Y, Li CY and Dewhirst MW: Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell. 5:429–441. 2004. View Article : Google Scholar : PubMed/NCBI
36	Chang IA, Oh MJ, Kim MH, Park SK, Kim BG and Namgung U: Vimentin phosphorylation by Cdc2 in schwann cell controls axon growth via β1-integrin activation. FASEB J. 26:2401–2413. 2012. View Article : Google Scholar : PubMed/NCBI
37	Chen WC, Hsu KY, Hung CM, Lin YC, Yang NS, Ho CT, Kuo SC and Way TD: The anti-tumor efficiency of pterostilbene is promoted with a combined treatment of Fas signaling or autophagy inhibitors in triple negative breast cancer cells. Food Funct. 5:1856–1865. 2014. View Article : Google Scholar : PubMed/NCBI
38	Nakajima E, Hammond KB, Rosales JL, Shearer TR and Azuma M: Calpain, not caspase, is the causative protease for hypoxic damage in cultured monkey retinal cells. Invest Ophthalmol Vis Sci. 52:7059–7067. 2011. View Article : Google Scholar : PubMed/NCBI