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Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress

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Abstract

Hypoxia can promote the progression and metastasis of ovarian cancer, while the underlying mechanisms are still unclear. Hypoxia culture or CoCl2 induced-oxygen deprivation condition could promote SKOV3 cells to express cyclooxygenase-2 (COX2). Luciferase assay indicates that hypoxia-inducible factor 1α (HIF1α) could bind directly with the promoter region of COX2 to promote the transcription. COX2 over-expressed SKOV3 cells show up-regulated stemness-related markers expression, proinflammatory gene expression, and increased tumor sphere formation. The inflammatory molecules (interleukin-6, C-X-C motif chemokine ligand 12, interleukin-1B, interleukin-10, and C-C motif chemokine ligand 2) and COX2 expression show positive correlations in the Cancer Genome Atlas data. COX2 over-expression could promote SKOV3 cell proliferation in the subcutaneous tumor model and metastasis in the transfer model. In conclusion, hypoxia-induced HIF-1α mediated COX2 expression could promote the proliferation, inflammation, and metastasis of ovarian cancer.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

References

  • Agarwal R (2003) The function of COX-2 in human ovarian carcinoma. Am J Pathol 163:368; author reply 368–369–369

    Article  Google Scholar 

  • Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G (2001) Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res: An Off J Am Assoc Cancer Res 7:1661–1668

    CAS  Google Scholar 

  • D’Ignazio L, Batie M, Rocha S (2017) Hypoxia and inflammation in cancer, focus on HIF and NF-kappaB. Biomedicines 5:21

    Article  Google Scholar 

  • Deng L, Feng DQ, Ling B (2020) Cyclooxygenase-2 promotes ovarian cancer cell migration and cisplatin resistance via regulating epithelial mesenchymal transition. J Zhejiang Univ Sci B 21:315–326

    Article  CAS  Google Scholar 

  • DiGiacomo JW, Gilkes DM (2018) Tumor hypoxia as an enhancer of inflammation-mediated metastasis: emerging therapeutic strategies. Target Oncol 13:157–173

    Article  Google Scholar 

  • DiGiacomo JW, Gilkes DM (2019) Therapeutic strategies to block the hypoxic response. Adv Exp Med Biol 1136:141–157

    Article  CAS  Google Scholar 

  • El Khoury L, Furie R (2019) Inflammatory arthritis: a unique presentation of human anaplasmosis. Clin Rheumatol 38:257–259

    Article  Google Scholar 

  • Flaum N, Crosbie EJ, Edmondson RJ, Smith MJ, Evans DG (2020) Epithelial ovarian cancer risk: a review of the current genetic landscape. Clin Genet 97:54–63

    Article  CAS  Google Scholar 

  • Gartung A, Yang J, Sukhatme VP, Bielenberg DR, Fernandes D, Chang J, Schmidt BA, Hwang SH, Zurakowski D, Huang S, Kieran MW, Hammock BD, Panigrahy D (2019) Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc Natl Acad Sci U S A 116:1698–1703

    Article  CAS  Google Scholar 

  • Gasparini G, Longo R, Sarmiento R, Morabito A (2003) Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 4:605–615

    Article  CAS  Google Scholar 

  • Harris RE (2015) Ibuprofen in the prevention and therapy of cancer. Ibuprofen: Discovery, Development and Therapeutics, John Wiley & Sons, pp 518–546

  • Horiuchi A, Hayashi T, Kikuchi N, Hayashi A, Fuseya C, Shiozawa T, Konishi I (2012) Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene. Int J Cancer 131:1755–1767

    Article  CAS  Google Scholar 

  • Icard P, Shulman S, Farhat D, Steyaert JM, Alifano M, Lincet H (2018) How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist Updates: Rev Commentaries Antimicrob Anticancer Chemother 38:1–11

    Article  Google Scholar 

  • Kaidi A, Qualtrough D, Williams AC, Paraskeva C (2006) Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Cancer Res 66:6683–6691

    Article  CAS  Google Scholar 

  • Kemilainen H, Huhtinen K, Auranen A, Carpen O, Strauss L, Poutanen M (2018) The expression of HSD17B12 is associated with COX-2 expression and is increased in high-grade epithelial ovarian cancer. Oncology 94:233–242

    Article  Google Scholar 

  • La Vecchia C (2017) Ovarian cancer: epidemiology and risk factors. Eur J Cancer Prev: The Off J Eur Cancer Prev Organ (ECP) 26:55–62

    Article  Google Scholar 

  • Lee HJ, Han HJ (2020) Role of microtubule-associated factors in HIF1alpha nuclear translocation. Adv Exp Med Biol 1232:271–276

    Article  CAS  Google Scholar 

  • Multhoff G, Vaupel P (2020) Hypoxia compromises anti-cancer immune responses. Adv Exp Med Biol 1232:131–143

    Article  CAS  Google Scholar 

  • Nasi ML, Castiglione M (2002) Cyclooxygenase-2 (COX-2) a new prognostic and predictive factor for ovarian cancer? Are all the criteria fulfilled? Ann Oncol: Off J Eur Soc Med Oncol 13:1169–1171

    Article  CAS  Google Scholar 

  • Pantshwa JM, Kondiah PPD, Choonara YE, Marimuthu T, Pillay V (2020) Nanodrug delivery systems for the treatment of ovarian cancer. Cancers 12:213

    Article  CAS  Google Scholar 

  • Roland IH, Yang WL, Yang DH, Daly MB, Ozols RF, Hamilton TC, Lynch HT, Godwin AK, Xu XX (2003) Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies. Cancer 98:2607–2623

    Article  Google Scholar 

  • Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  Google Scholar 

  • Sethi G, Shanmugam MK, Ramachandran L, Kumar AP, Tergaonkar V (2012) Multifaceted link between cancer and inflammation. Biosci Rep 32:1–15

    Article  CAS  Google Scholar 

  • Vaupel P, Multhoff G (2020) Fatal alliance of hypoxia-/HIF-1alpha-driven microenvironmental traits promoting cancer progression. Adv Exp Med Biol 1232:169–176

    Article  CAS  Google Scholar 

  • Wang YP, Wang QY, Li CH, Li XW (2018) COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced snail nuclear translocation. Chem Biol Interact 292:24–29

    Article  CAS  Google Scholar 

  • Wendel JRH, Wang X, Hawkins SM (2018) The endometriotic tumor microenvironment in ovarian cancer. Cancers 10:261

    Article  Google Scholar 

  • Yeh YH, Hsiao HF, Yeh YC, Chen TW, Li TK (2018) Inflammatory interferon activates HIF-1a-mediated epithelial-to-mesenchymal transition via PI3K/AKT/mTOR pathway. J Exp Clin Cancer Res 37:70

  • Zhang T, Suo C, Zheng C, Zhang H (2019) Hypoxia and metabolism in metastasis. Adv Exp Med Biol 1136:87–95

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gynaecology, ZIBO Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255036, Shandong, China

    Yumei Ding, Shichao Zhuang, Yujiao Li, Xiaohui Yu, Ming Lu & Ning Ding

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  1. Yumei Ding
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  2. Shichao Zhuang
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  3. Yujiao Li
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  4. Xiaohui Yu
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  5. Ming Lu
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  6. Ning Ding
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Correspondence to Ning Ding.

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All animal studies were approved by the Ethical Commitment of ZIBO Central Hospital.

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Ding, Y., Zhuang, S., Li, Y. et al. Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress. J Bioenerg Biomembr 53, 441–448 (2021). https://doi.org/10.1007/s10863-021-09900-9

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  • DOI: https://doi.org/10.1007/s10863-021-09900-9

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