Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea

Campillo, Noelia; Torres, Marta; Vilaseca, Antoni; Nonaka, Paula Naomi; Gozal, David; Roca‐Ferrer, Jordi; Picado, César; Montserrat, Josep M.; Farré, Ramón; Navajas, Daniel; Almendros, Isaac

doi:10.1038/srep44693

Cited by 38 publications

(31 citation statements)

References 52 publications

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“…In a recent study by Gautier-Veyret and collaborators, COX-1 was activated in mice exposed to CIH, and treatment with a specific COX-1 inhibitor reduced the magnitude of CIH-induced lesions in the aorta (Gautier-Veyret et al, 2013). Increased levels of COX metabolites have been consistently reported in response to cyclic hypoxia by several cell types including endothelial cells (Li et al, 2003;Daneau et al, 2010;Tang et al, 2014), vascular smooth muscle cells (Tang et al, 2014) and immune cells (Campillo et al, 2017). Furthermore, clinical studies have associated COX-activity with common carotid artery intima media thickness (CCA-IMT).…”

Section: Discussionmentioning

confidence: 96%

Acetylsalicylic Acid Prevents Intermittent Hypoxia-Induced Vascular Remodeling in a Murine Model of Sleep Apnea

Suárez-Girón

Torres

Montserrat

et al. 2018

Sleep and Control of Breathing

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Study objectives: Chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA), induces accelerated atherogenesis as well as aorta vascular remodeling. Although the cyclooxygenase (COX) pathway has been proposed to contribute to the cardiovascular consequences of OSA, the potential benefits of a widely employed COX-inhibitor such (acetylsalicylic acid, ASA) on CIH-induced vascular pathology are unknown. Therefore, we hypothesized that a common non-selective COX inhibitor such as ASA would attenuate the aortic remodeling induced by CIH in mice. Methods: 40 wild-type C57/BL6 male mice were randomly allocated to CIH or normoxic exposures (N) and treated with daily doses of ASA or placebo for 6 weeks. At the end of the experiments, intima-media thickness (IMT), elastin disorganization (ED), elastin fragmentation (EF), length between fragmented fiber endpoints (LFF), aortic wall collagen abundance (AC) and mucoid deposition (MD) were assessed. Results: Compared to N, CIH promoted significant increases in IMT (52.58 ± 2.82 µm vs. 46.07 ± 4.18 µm, p < 0.003), ED (25.29 ± 14.60% vs. 4.74 ± 5.37%, p < 0.001), EF (5.80 ± 2.04 vs. 3.06 ± 0.58, p < 0.001), LFF (0.65 ± 0.34% vs. 0.14 ± 0.09%, p < 0.001), AC (3.43 ± 1.52% vs. 1.67 ± 0.67%, p < 0.001) and MD (3.40 ± 2.73 µm 2 vs. 1.09 ± 0.72 µm 2 , p < 0.006). ASA treatment mitigated the CIH-induced alterations in IMT: 44.07 ± 2.73 µm; ED: 10.57 ± 12.89%; EF: 4.63 ± 0.88; LFF: 0.25 ± 0.17% and AC: 0.90 ± 0.13% (p<0.05 for all comparisons). Conclusions: ASA prevents the CIH-induced aortic vascular remodeling, and should therefore be prospectively evaluated as adjuvant treatment in patients with OSA.

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Section: Discussionmentioning

confidence: 96%

Acetylsalicylic Acid Prevents Intermittent Hypoxia-Induced Vascular Remodeling in a Murine Model of Sleep Apnea

Suárez-Girón

Torres

Montserrat

et al. 2018

Sleep and Control of Breathing

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“…One proposed mechanism involves CIH induced activation of many transcriptional factors, such as HIF-1α, activator protein-1, nuclear factor kappa-light-chain-enhancer of activated B cells and Nrf2, and expression of specific genes associated with tumorigenesis 30 . The immune response is another important component of the tumor microenvironment, and immune cell activities are suggested as potential mechanisms linking OSA and cancer 10 .…”

Section: Discussionmentioning

confidence: 99%

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

Kang

Kwon

Kim

et al. 2020

Sci Rep

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the purpose of this study was to evaluate whether obstructive sleep apnea (oSA)-related chronic intermittent hypoxia (CIH) influences lung cancer progression and to elucidate the associated mechanisms in a mouse model of lung cancer. C57/BL6 mice in a CIH group were exposed to intermittent hypoxia for two weeks after tumor induction and compared with control mice (room air). Hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VeGf) and metastasis-related matrix metalloproteinases (MMp) were measured. the expression levels of several hypoxia-related pathway proteins including HIF-1α, Wnt/ß-catenin, the nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin-eRK were measured by western blot. the number (p < 0.01) and volume (p < 0.05) of tumors were increased in the CIH group. The activity of MMP-2 was enhanced after CIH treatment. The level of VEGF was increased significantly in the CIH group (p < 0.05). ß-catenin and Nrf2 were translocated to the nucleus and the levels of downstream effectors of Wnt/ß-catenin signaling increased after iH exposure. ciH enhanced proliferative and migratory properties of tumors in a mouse model of lung cancer. ß-catenin and Nrf2 appeared to be crucial mediators of tumor growth. Obstructive sleep apnea (OSA) is characterized by recurrent occlusion of the upper airway during sleep leading to chronic intermittent hypoxia (CIH). OSA is a highly prevalent sleep disorder affecting at least 3% to 7% of the adult population 1. OSA has been shown to be associated with morbidities including metabolic syndrome, systemic hypertension, pulmonary vascular disease, ischemic heart disease and congestive heart failure 2. In addition, OSA-related CIH has been suggested to affect tumor development and progression 3. OSA has been implicated in the increasing incidence of certain types of solid malignancies. In a Spanish cohort, increased overnight hypoxia as a surrogate of OSA severity was associated with increased cancer incidence in selected populations 4-6. Also, OSA was associated with increased cancer mortality in a community-based sample 7. The association between OSA and lung cancer has been evaluated. OSA-related CIH induced resistance to apoptosis and increased metastasis in lung cancer cells, in a manner related to hypoxia inducible factor 1α (HIF-1α) 8. The role of immune cells has been suggested as a potential mechanism linking OSA and cancer. Almendros et al. demonstrated that CIH induced changes in host immune responses are related to adverse cancer outcomes. CIH increases the mobilization of tumor-associated macrophages (TAMs) into tumors, and induces macrophages to transform from an anti-tumor phenotype (M1) to a tumor-promoting phenotype (M2) 9. Cyclooxygenase-2 inhibited IH-induced M2 polarization of TAMs and prevented IH-induced adverse tumor outcomes in a mouse model of sleep apnea 10. OSA-related CIH altered CD8 + T-cells in combination with changes in the tumor microenvironment that enhanced malignant tumor properties 11. Studies...

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“…The results demonstrated that the effects of HPV16 E6 in promoting breast cancer proliferation were achieved by the upregulation of COX-2. It has been reported that COX-2 plays important roles in the carcinogenesis and development of many tumors including breast cancer [ 25 – 27 ]. In the past few years, The animal experiments in vivo clearly indicate that high COX-2 expression is correlated to the genesis of mammary tumors that are sensitive to treatment with nonselective and selective COX-2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

HPV16 E6 Promotes Breast Cancer Proliferation via Upregulation of COX-2 Expression

Wang

Zhang

et al. 2017

BioMed Research International

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Background. Breast cancer remains the leading cause of cancer-related mortality worldwide. It has been indicated that human papillomaviruses 16 (HPV16) might participate in the pathogenesis and development of breast cancer. However, the detected rate of HPV16 varies with region. We will investigate HPV16 E6 expression in North China and explore the effects and mechanism of HPV16 E6 on breast cancer proliferation in this study. Methods. The expressions of HPV16 E6 and COX-2 in paraffin-embedded tissues of the invasive ductal breast cancer were detected by qPCR and IHC. The effects of HPV16 E6 on breast cancer proliferation were determined by function studies. The mechanism of HPV16 E6 in promoting breast cancer proliferation was explored by Western blot and Dual-Luciferase Reporter Assay. Results. HPV16 E6 was positive in 28% invasive ductal breast carcinoma in North China; HPV16 E6 promoted breast cancer proliferation. Inhibition of COX-2 by siCOX-2 or Celecoxib attenuated the proliferation of breast cancer cells with HPV16 E6 expression; and the upregulation of COX-2 could be suppressed by the inhibition of NF-κB activity. Conclusion. HPV16 E6 promotes breast cancer proliferation by activation of NF-κB signaling pathway and increase of COX-2 expression. COX-2 will be a potential target for HPV16 E6-associated breast cancer.

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Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea

Cited by 38 publications

References 52 publications

Acetylsalicylic Acid Prevents Intermittent Hypoxia-Induced Vascular Remodeling in a Murine Model of Sleep Apnea

Acetylsalicylic Acid Prevents Intermittent Hypoxia-Induced Vascular Remodeling in a Murine Model of Sleep Apnea

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

HPV16 E6 Promotes Breast Cancer Proliferation via Upregulation of COX-2 Expression

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