Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer

Ji,Fang; Wang,You; Qiu,Lihua; Li,Shu; Zhu,Jing; Liang,Zhou; Wan,Yinsheng; Di,Wen

doi:10.3892/ijo.2013.1878

Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer

Authors:
- Fang Ji
- You Wang
- Lihua Qiu
- Shu Li
- Jing Zhu
- Zhou Liang
- Yinsheng Wan
- Wen Di
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China, Department of Biology, Providence College, Providence, RI 02918, USA
Published online on: March 29, 2013 https://doi.org/10.3892/ijo.2013.1878
Pages: 1578-1588

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

This study investigated the role of LOX in promoting invasion and metastasis of epithelial ovarian cancer in a hypoxic environment and its specific signal transduction pathway. Immunohistochemical detection of HIF-1α and LOX protein expression was performed on formalin-fixed paraffin sections of normal ovary, benign ovarian tumors, borderline and malignant epithelial ovarian tumor paraffin sample, using Mann-Whitney U test for independent comparisons and Wilcoxon signed-ranks test for paired comparisons. HIF-1α and LOX were knocked down in epithelial ovarian cancer cells (EOC), and HIF-1α/LOX regulation mechanism and LOX catalytic activity under hypoxia/reoxygenation microenvironment were explored. Cell migration and invasion ability in LOX inhibited HO8910 cells were investigated under hypoxia/reoxygenation conditions, using matrigel cell invasion and migration assays. We found that HIF-1α and LOX are highly expressed in epithelial ovarian cancer tissues, and the expression of both proteins is significantly correlated with the tumor grade, tumor diameter and lymph node metastasis. HIF-1α expression is positively correlated with the expression of LOX. Specifically, the expression of LOX and HIF-1α markedly increases under hypoxic conditions and decreases after reoxygenation. siRNA knockdown of LOX or β-aminoproprionitrile (βAPN), an inhibitor of LOX activity, that attenuates LOX activity, downregulates HIF-1α protein expression and inhibits HO8910 migratory and invasive abilities. LOX catalytic activity is significantly reduced under hypoxic conditions. Moreover, EOC cells display a marked increase in LOX-dependent FAK/AKT activation and cell migration following hypoxia/reoxygenation. Collectively, our study demonstrates that the hypoxia-HIF-1α, LOX-FAK/AKT pathway regulates the migration and invasion of epithelial ovarian cancer cells under hypoxia/reoxygenation conditions, thus, promoting metastasis of ovarian cancer.

View Figures

View References

1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2.	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar
3.	Rustin G, van der Burg M, Griffin C, Qian W and Swart AM: Early versus delayed treatment of relapsed ovarian cancer. Lancet. 377:380–381. 2011. View Article : Google Scholar : PubMed/NCBI
4.	Vergara D, Merlot B, Lucot JP, Collinet P, Vinatier D, Fournier I and Salzet M: Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett. 291:59–66. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Ricciardelli C and Oehler MK: Diverse molecular pathways in ovarian cancer and their clinical significance. Maturitas. 62:270–275. 2009. View Article : Google Scholar : PubMed/NCBI
6.	Choi JY, Jang YS, Min SY and Song JY: Overexpression of MMP-9 and HIF-1α in breast cancer cells under hypoxic conditions. J Breast Cancer. 14:88–95. 2011.
7.	Dayan F, Mazure NM, Brahimi-Horn MC and Pouyssegur J: A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron. 1:53–68. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Allen M and Louise Jones J: Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol. 223:162–176. 2011. View Article : Google Scholar : PubMed/NCBI
9.	Semenza GL: Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 29:625–634. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Chen CL, Chu JS, Su WC, Huang SC and Lee WY: Hypoxia and metabolic phenotypes during breast carcinogenesis: expression of HIF-1alpha, GLUT1, and CAIX. Virchows Arch. 457:53–61. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Lucero HA and Kagan HM: Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci. 63:2304–2316. 2006. View Article : Google Scholar : PubMed/NCBI
12.	Payne SL, Hendrix MJ and Kirschmann DA: Paradoxical roles for lysyl oxidases in cancer - a prospect. J Cell Biochem. 101:1338–1354. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Postovit LM, Abbott DE, Payne SL, Wheaton WW, Margaryan NV, Sullivan R, Jansen MK, Csiszar K, Hendrix MJ and Kirschmann DA: Hypoxia/reoxygenation: a dynamic regulator of lysyl oxidase-facilitated breast cancer migration. J Cell Biochem. 103:1369–1378. 2008. View Article : Google Scholar : PubMed/NCBI
14.	Nagaraja GM, Othman M, Fox BP, Alsaber R, Pellegrino CM, Zeng Y, Khanna R, Tamburini P, Swaroop A and Kandpal RP: Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene. 25:2328–2338. 2006. View Article : Google Scholar
15.	Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS and Giaccia AJ: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440:1222–1226. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ and Kirschmann DA: Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res. 65:11429–11436. 2005. View Article : Google Scholar : PubMed/NCBI
17.	Polgar N, Fogelgren B, Shipley JM and Csiszar K: Lysyl oxidase interacts with hormone placental lactogen and synergistically promotes breast epithelial cell proliferation and migration. J Biol Chem. 282:3262–3272. 2007. View Article : Google Scholar : PubMed/NCBI
18.	Fogelgren B, Polgar N, Szauter KM, Ujfaludi Z, Laczko R, Fong KS and Csiszar K: Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. J Biol Chem. 280:24690–24697. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Bouez C, Reynaud C, Noblesse E, Thepot A, Gleyzal C, Kanitakis J, Perrier E, Damour O and Sommer P: The lysyl oxidase LOX is absent in basal and squamous cell carcinomas and its knockdown induces an invading phenotype in a skin equivalent model. Clin Cancer Res. 12:1463–1469. 2006. View Article : Google Scholar : PubMed/NCBI
20.	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
21.	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar
22.	Cassavaugh J and Lounsbury KM: Hypoxia-mediated biological control. J Cell Biochem. 112:735–744. 2011. View Article : Google Scholar : PubMed/NCBI
23.	Gort EH, Groot AJ, van der Wall E, van Diest PJ and Vooijs MA: Hypoxic regulation of metastasis via hypoxia-inducible factors. Curr Mol Med. 8:60–67. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Rofstad EK: Microenvironment-induced cancer metastasis. Int J Radiat Biol. 76:589–605. 2000. View Article : Google Scholar : PubMed/NCBI
25.	Ruan K, Song G and Ouyang G: Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 107:1053–1062. 2009. View Article : Google Scholar : PubMed/NCBI
26.	Pez F, Dayan F, Durivault J, Kaniewski B, Aimond G, Le Provost GS, Deux B, Clezardin P, Sommer P, Pouyssegur J and Reynaud C: The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. Cancer Res. 71:1647–1657. 2011. View Article : Google Scholar : PubMed/NCBI
27.	Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R and Giaccia AJ: Investigating hypoxic tumor physiology through gene expression patterns. Oncogene. 22:5907–5914. 2003. View Article : Google Scholar : PubMed/NCBI
28.	Choi YK, Kim CK, Lee H, Jeoung D, Ha KS, Kwon YG, Kim KW and Kim YM: Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein. J Biol Chem. 285:32116–32125. 2010. View Article : Google Scholar