Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress

Ding, Yong Hong; Zhuang, Shichao; Li, Yujiao; Yu, Xiaohui; Lü, Ming; Ding, Ning

doi:10.1007/s10863-021-09900-9

Cited by 14 publications

(7 citation statements)

References 27 publications

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“…Spatial expression of COX-2 in GBM shows that the majority of COX-2 expression is localized to the core of the tumor, dissipating in the periphery, and is negligible in adjacent tissues. This pattern of expression is consistent with the fact that GBM characteristically maintains a hypoxic microenvironment particularly in the central regions of tumor and hypoxia facilitates COX-2 upregulation in a HIF-1α dependent manner ( 60 , 74 ).…”

Section: Pge2/ep2 Signalingsupporting

confidence: 84%

“…LPS/TLR4 activation also triggers MyD88-dependent activation of tumor progression locus 2 (Tpl2), which leads to nuclear translocation and activation of both NFκB and CREB. In addition to receptor-stimulated regulation, COX-2 expression can be upregulated by hypoxia, which triggers NF-κB interaction with the NF-κB regulatory element and recruitment of Hypoxia Inducible Factor 1α (HIF-1α) to the COX-2 promoter ( 59 , 60 ). Finally, Nitric oxide (NO), a small molecule converted from L-arginine by inducible nitric oxide synthase (iNOS), can enhance COX-2 expression through activation of CREB ( 61 ).…”

Section: Cox-2: Activity and Expressionmentioning

confidence: 99%

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Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment

Dean

Hooks

2023

Front. Oncol.

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Glioblastoma (GBM) is the most common and aggressive form of malignant glioma. The GBM tumor microenvironment (TME) is a complex ecosystem of heterogeneous cells and signaling factors. Glioma associated macrophages and microglia (GAMs) constitute a significant portion of the TME, suggesting that their functional attributes play a crucial role in cancer homeostasis. In GBM, an elevated GAM population is associated with poor prognosis and therapeutic resistance. Neoplastic cells recruit these myeloid populations through release of chemoattractant factors and dysregulate their induction of inflammatory programs. GAMs become protumoral advocates through production a variety of cytokines, inflammatory mediators, and growth factors that can drive cancer proliferation, invasion, immune evasion, and angiogenesis. Among these inflammatory factors, cyclooxygenase-2 (COX-2) and its downstream product, prostaglandin E2 (PGE2), are highly enriched in GBM and their overexpression is positively correlated with poor prognosis in patients. Both tumor cells and GAMs have the ability to signal through the COX-2 PGE2 axis and respond in an autocrine/paracrine manner. In the GBM TME, enhanced signaling through the COX-2/PGE2 axis leads to pleotropic effects that impact GAM dynamics and drive tumor progression.

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Section: Pge2/ep2 Signalingsupporting

confidence: 84%

Section: Cox-2: Activity and Expressionmentioning

confidence: 99%

Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment

Dean

Hooks

2023

Front. Oncol.

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“…One notable phenotype of immunologically suppressed tumors that we observed was the interplay between NK cells, DC and COX-2, where we observed reduced signature scores for cDC1, lower MCP-counter abundance scores for myeloid DC and NK cells, as well as the increased gene expression of COX-2 ( PTGS2 ) in Hypoxia HI vs Hypoxia LOW cases ( Figures 3 , 5 and Supplementary Figure 5 ). The induction of COX-2 expression in hypoxic conditions has been reported in both colon cancer and ovarian cancer cells ( 81 , 82 ). Moreover, while COX-2 is reported to have tumor-intrinsic roles in the development and progression of PDAC in murine models ( 83 ), recent findings also demonstrated a key role for COX-2 in hindering anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 98%

High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment

Sadozai,

Acharjee,

Kayani

et al. 2024

Front. Immunol.

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IntroductionPancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression.MethodsWe used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions.ResultsFirst, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines.DiscussionIn summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.

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“…The HYPOXIA pathway can affect FAO and transport rates [53]. Hypoxic partial pressure can activate the 'HYPOXIA' signaling pathway of OC, enhance tumor cell proliferation and metastasis [54], and induce increased PDK4 gene expression [55]. The low-risk group was dominated by the activation of signaling pathways such as 'PI3K/AKT/MTOR SIGNALING'.…”

Section: Discussionmentioning

confidence: 99%

Correlation analysis of fatty acid metabolism-related genes and the prognosis of ovarian cancer

Zhou,

Meng

et al. 2024

Preprint

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Background Increasing evidence suggests that abnormal fatty acid metabolism (FAM) is a switch triggering tumor progression. The aim of this study was to explore the prognostic value of FAM-related genes (FAMRGs) in serous ovarian cancer (SOC) by bioinformatics analysis and to develop a novel FAM-related prognostic signature. Methods Clinicopathological characteristics and FAMRGs were obtained from The Cancer Genome Atlas database and the Molecular Signatures Database. The limma R package and Cox regression were used to determine the FAM-related signature. The Kaplan-Meier curve and Cox regression were used to evaluate the prognostic value of the risk score, after which gene set variation analysis was performed to explore the biological functions. The immune cell infiltration level was analyzed. The potential response to immune checkpoint inhibitor (ICI) therapy was evaluated by the tumor immune dysfunction and exclusion algorithm. Finally, RT-PCR analysis was performed to measure the expression levels of 9 prognostic genes. Results Nine FAMRGs that were significantly associated with SOC prognosis were screened out, and a robust risk scoring model was constructed. This risk score was also an independent prognostic factor for patients with SOC. Patients with high-risk scores were characterized by poor clinical outcomes, lower levels of immune cell infiltration, and elevated TIDE scores. In addition, patients with low-risk scores may be better candidates for ICI therapy. Conclusions Our data suggest that the abnormal expression of 9 FAM-related genes is closely related to the progression of SOC. Moreover, a novel FAM-related prognostic signature may contribute to immunotherapy consultation for SOC.

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Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress

Cited by 14 publications

References 27 publications

Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment

Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment

High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment

Correlation analysis of fatty acid metabolism-related genes and the prognosis of ovarian cancer

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