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Article

Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis

  • Authors:
    • Da Zhai
    • Yong Xu
    • Lina Abdelghany
    • Xu Zhang
    • Jingyan Liang
    • Shouhua Zhang
    • Changying Guo
    • Tao-Sheng Li
  • View Affiliations / Copyright

    Affiliations: Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852‑8523, Japan, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China, Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi 330000, P.R. China, Department of Thoracic Surgery, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330000, P.R. China
  • Article Number: 211
    |
    Published online on: July 30, 2021
       https://doi.org/10.3892/or.2021.8162
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Abstract

The tissue microenvironment is known to play a pivotal role in cancer metastasis. Interstitial fluid hydrostatic pressure generally increases along with the rapid growth of malignant tumors. The aim of the present study was to investigate the role and relevant mechanism of elevated hydrostatic pressure in promoting the metastasis of cancer cells. Using a commercial device, Lewis lung cancer (LLC) cells were exposed to 50 mmHg hydrostatic pressure (HP) for 24 h. The survival time and morphology of the cells did not notably change; however, the results from a PCR array revealed the upregulation of numerous metastasis‑promoting genes (Hgf, Cdh11 and Ephb2) and the downregulation of metastasis suppressing genes (Kiss1, Syk and Htatip2). In addition, compared with that in the control, the cells which had undergone exposure to 50 mmHg HP showed significantly higher protein expression level of HIF‑1α and the antioxidant enzymes, SOD1 and SOD2, as well as improved tolerance to oxidative stress (P<0.05 vs. control). Following an intravenous injection of the LLC cells into healthy mice, to induce lung metastasis, it was found that the exposure of the LLC cells to 50 mmHg HP for 24 h, prior to injection into the mice, resulted in higher cell survival/retention in the lungs 24 h later and also resulted in more metastatic tumor lesions 4 weeks later (P<0.05 vs. control). Further investigation is required to confirm the molecular mechanism; however, the results from the present study suggested that elevated interstitial fluid HP in malignant tumors may promote the metastasis of cancer cells by stabilizing HIF‑1α expression to defend against oxidative damage.
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1 

Brabletz T, Lyden D, Steeg PS and Werb Z: Roadblocks to translational advances on metastasis research. Nat Med. 19:1104–1109. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Bregenzer ME, Horst EN, Mehta P, Novak CM, Repetto T and Mehta G: The role of cancer stem cells and mechanical forces in ovarian cancer metastasis. Cancers. 11:10082019. View Article : Google Scholar : PubMed/NCBI

3 

Eccles SA and Welch DR: Metastasis: Recent discoveries and novel treatment strategies. Lancet. 369:1742–1757. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Fidler IJ: The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Zijl FV, Krupitza G and Mikulits W: Initial steps of metastasis: Cell invasion and endothelial transmigration. Mutat Res. 728:23–34. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ and Morrison SJ: Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 527:186–191. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Vanharanta S and Massague J: Origins of metastatic traits. Cancer Cell. 24:410–421. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Kao YC, Jheng JR, Pan HJ, Liao WY, Lee CH and Kuo PL: Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signaling. Oncogene. 36:863–874. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y, Jain RK and Munn LL: Mechanical compression drives cancer cells toward invasive phenotype. Proc Natl Acad Sci USA. 109:911–916. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Less JR, Posner MC, Boucher Y, Borochovitz D, Wolmark N and Jain RK: Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 52:6371–6374. 1992.PubMed/NCBI

11 

Nathan SS, DiResta GR, Casas-Ganem JE, Hoang BH, Sowers R, Yang R, Huvos AG, Gorlick R and Healey JH: Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clin Cancer Res. 11:2389–2397. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Gutmann R, Leunig M, Feyh J, Goetz AE, Messmer K, Kastenbauer E and Jain RK: Interstitial hypertension in head and neck tumors in patients: Correlation with tumor size. Cancer Res. 52:1993–1995. 1992.PubMed/NCBI

13 

Solis AG, Bielecki P, Steach HR, Sharma L, Harman CC, Yun S, de Zoete MR, Warnock JN, To SDF, York AG, et al: Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature. 573:69–74. 2019. View Article : Google Scholar : PubMed/NCBI

14 

Rankin EB, Nam JM and Giaccia AJ: Hypoxia: Signaling the metastatic cascade. Trends Cancer. 2:295–304. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Semenza GL: Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 19:12–16. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Urata Y, Goto S, Luo L, Doi H, Kitajima Y, Masuda S, Ono Y and Li TS: Enhanced Nox1 expression and oxidative stress resistance in c-kit-positive hematopoietic stem/progenitor cells. Biochem Biophys Res Commun. 454:376–380. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Hu XQ, Song R and Zhang L: Effect of oxidative stress on the estrogen-NOS-NO-KCa channel pathway in uteroplacental dysfunction: Its implication in pregnancy complications. Oxid Med Cell Longev. 2019:91942692019. View Article : Google Scholar : PubMed/NCBI

19 

Novak S, Drenjancevic I, Vukovic R, Kellermayer Z, Cosic A, Tolusic Levak M, Balogh P, Culo F and Mihalj M: Anti-inflammatory effects of hyperbaric oxygenation during DSS-induced colitis in BALB/c mice include changes in gene expression of HIF-1α, proinflammatory cytokines, and antioxidative enzymes. Mediators Inflamm. 2016:71414302016. View Article : Google Scholar : PubMed/NCBI

20 

Jain RK, Martin JD and Stylianopoulos T: The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng. 16:321–346. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS and Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 219:983–985. 1983. View Article : Google Scholar : PubMed/NCBI

22 

Liu YL, Horning AM, Lieberman B, Kim M, Lin CK, Hung CN, Chou CW, Wang CM, Lin CL, Kirma NB, et al: Spatial EGFR dynamics and metastatic phenotypes modulated by upregulated EphB2 and Src pathways in advanced prostate cancer. Cancers (Basel). 11:19102019. View Article : Google Scholar : PubMed/NCBI

23 

Sato S, Vasaikar S, Eskaros A, Kim Y, Lewis JS, Zhang B, Zijlstra A and Weaver AM: EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling. JCI Insight. 4:e1324472019. View Article : Google Scholar : PubMed/NCBI

24 

Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, Boxer LA, Bonilla MA, Newburger PE, Shimamura A, et al: The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 22:3–11. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Nakashima R, Goto Y, Koyasu S, Kobayashi M, Morinibu A, Yoshimura M, Hiraoka M, Hammond EM and Harada H: UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization. Sci Rep. 7:68792017. View Article : Google Scholar : PubMed/NCBI

26 

Semenza GL: Pharmacologic targeting of hypoxia-inducible factors. Annu Rev Pharmacol Toxicol. 59:379–403. 2019. View Article : Google Scholar : PubMed/NCBI

27 

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI

28 

Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ and Harris AL: The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 157:411–421. 2000. View Article : Google Scholar : PubMed/NCBI

29 

Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, Bersiga A, Allevi G, Milani M, Aguggini S, et al: Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res. 12:4562–4568. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH and Semenza GL: Expression of hypoxia-inducible factor-1alpha: A novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 61:2911–2916. 2001.PubMed/NCBI

31 

Nanni S, Benvenuti V, Grasselli A, Priolo C, Aiello A, Mattiussi S, Colussi C, Lirangi V, Illi B, D'Eletto M, et al: Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest. 119:1093–1108. 2009. View Article : Google Scholar : PubMed/NCBI

32 

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

33 

Apte RS, Chen DS and Ferrara N: VEGF in signaling and disease: Beyond discovery and development. Cell. 176:1248–1264. 2019. View Article : Google Scholar : PubMed/NCBI

34 

Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 20:4368–4380. 2002. View Article : Google Scholar : PubMed/NCBI

35 

Kellar A, Egan C and Morris D: Preclinical murine models for lung cancer: Clinical trial applications. Biomed Res Int. 2015:6213242015. View Article : Google Scholar : PubMed/NCBI

36 

Mori T, Koga T, Shibata H, Ikeda K, Shiraishi K, Suzuki M and Iyama K: Interstitial fluid pressure correlates clinicopathological factors of lung cancer. Ann Thorac Cardiovasc Surg. 21:201–208. 2015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhai D, Xu Y, Abdelghany L, Zhang X, Liang J, Zhang S, Guo C and Li T: Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis. Oncol Rep 46: 211, 2021.
APA
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S. ... Li, T. (2021). Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis. Oncology Reports, 46, 211. https://doi.org/10.3892/or.2021.8162
MLA
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S., Guo, C., Li, T."Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis". Oncology Reports 46.4 (2021): 211.
Chicago
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S., Guo, C., Li, T."Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis". Oncology Reports 46, no. 4 (2021): 211. https://doi.org/10.3892/or.2021.8162
Copy and paste a formatted citation
x
Spandidos Publications style
Zhai D, Xu Y, Abdelghany L, Zhang X, Liang J, Zhang S, Guo C and Li T: Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis. Oncol Rep 46: 211, 2021.
APA
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S. ... Li, T. (2021). Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis. Oncology Reports, 46, 211. https://doi.org/10.3892/or.2021.8162
MLA
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S., Guo, C., Li, T."Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis". Oncology Reports 46.4 (2021): 211.
Chicago
Zhai, D., Xu, Y., Abdelghany, L., Zhang, X., Liang, J., Zhang, S., Guo, C., Li, T."Hydrostatic pressure stabilizes HIF‑1α expression in cancer cells to protect against oxidative damage during metastasis". Oncology Reports 46, no. 4 (2021): 211. https://doi.org/10.3892/or.2021.8162
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