Preliminary Analysis of the Expression of Selected Proangiogenic and Antioxidant Genes and MicroRNAs in Patients with Non-Muscle-Invasive Bladder Cancer

Kozakowska, Magdalena; Dobrowolska-Glazar, Barbara; Okoń, Krzysztof; Józkowicz, Alicja; Dobrowolski, Zbysław; Dulak, Józef

doi:10.3390/jcm5030029

Cited by 23 publications

(16 citation statements)

References 69 publications

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“…Moreover, both NRF2 and HIF-1α have overlapping transcriptional targets, such as HMOX1 , NQO1 , G6PD , PGK , TALDO , SLC7A11 , PDGFC , FGF2 , etc. (Toth and Warfel, 2017, Kozakowska et al, 2016). It was shown recently that hypoxia induces PIM1 and PIM2, which positively regulate HIF-1α protein levels under hypoxia and the cellular localization of NRF2 under both hypoxia and normoxia (Warfel et al, 2016).…”

Section: Nrf2 and The Hallmarks Of Cancermentioning

confidence: 99%

NRF2 and the Hallmarks of Cancer

2018

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The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects.

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Section: Nrf2 and The Hallmarks Of Cancermentioning

confidence: 99%

NRF2 and the Hallmarks of Cancer

2018

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“…NRF2 also indirectly regulates HIF-1a levels by preventing its proteasomal degradation by the aid of NQO1 [161,182]. Angiogenesis is also regulated by common effectors of NRF2 and HIF1a including HO-1, platelet-derived growth factor (PDGFC), and fibroblast growth factor (FGF2) [183][184][185]. Among these genes, HMOX1 was shown to promote angiogenesis in various cancers such as glioma, pancreatic cancer, and melanoma [176,186].…”

Section: Angiogenesis Inductionmentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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“…In bladder cancer tissue, the overexpression of HO-1 was correlated with the increased expression of Nrf2, HIF-1α, HIF-2α, and VEGFA. In sera of bladder cancer patients, the pro-inflammatory cytokines IL-6 and IL-8 were also elevated, along with the pro-angiogenic factor VEGFA [53].…”

Section: The Nrf2 Involvement In Cancer Development and Progressionmentioning

confidence: 99%

The Role of Nrf2 Activity in Cancer Development and Progression

Zimța

Cenariu

Irimie

et al. 2019

Cancers

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Nrf2 is a transcription factor that stimulates the expression of genes which have antioxidant response element-like sequences in their promoter. Nrf2 is a cellular protector, and this principle applies to both normal cells and malignant cells. While healthy cells are protected from DNA damage induced by reactive oxygen species, malignant cells are defended against chemo- or radiotherapy. Through our literature search, we found that Nrf2 activates several oncogenes unrelated to the antioxidant activity, such as Matrix metallopeptidase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large (BCL-xL), Tumour Necrosis Factor α (TNF-α), and Vascular endothelial growth factor A (VEGF-A). We also did a brief analysis of The Cancer Genome Atlas (TCGA) data of lung adenocarcinoma concerning the effects of radiation therapy and found that the therapy-induced Nrf2 activation is not universal. For instance, in the case of recurrent disease and radiotherapy, we observed that, for the majority of Nrf2-targeted genes, there is no change in expression level. This proves that the universal, axiomatic rationale that Nrf2 is activated as a response to chemo- and radiation therapy is wrong, and that each scenario should be carefully evaluated with the help of Nrf2-targeted genes. Moreover, there were nine genes involved in lipid peroxidation, which showed underexpression in the case of new radiation therapy: ADH1A, ALDH3A1, ALDH3A2, ADH1B, GPX2, ADH1C, ALDH6A1, AKR1C3, and NQO1. This may relate to the fact that, while some studies reported the co-activation of Nrf2 and other oncogenic signaling pathways such as Phosphoinositide 3-kinases (PI3K), mitogen-activated protein kinase (MAPK), and Notch1, other reported the inverse correlation between Nrf2 and the tumor-promoter Transcription Factor (TF), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Lastly, Nrf2 establishes its activity through interactions at multiple levels with various microRNAs. MiR-155, miR-144, miR-28, miR-365-1, miR-93, miR-153, miR-27a, miR-142, miR-29-b1, miR-340, and miR-34a, either through direct repression of Nrf2 messenger RNA (mRNA) in a Kelch-like ECH-associated protein 1 (Keap1)-independent manner or by enhancing the Keap1 cellular level, inhibit the Nrf2 activity. Keap1–Nrf2 interaction leads to the repression of miR-181c, which is involved in the Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling pathway. Nrf2’s role in cancer prevention, diagnosis, prognosis, and therapy is still in its infancy, and the future strategic planning of Nrf2-based oncological approaches should also consider the complex interaction between Nrf2 and its various activators and inhibitors.

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Preliminary Analysis of the Expression of Selected Proangiogenic and Antioxidant Genes and MicroRNAs in Patients with Non-Muscle-Invasive Bladder Cancer

Cited by 23 publications

References 69 publications

NRF2 and the Hallmarks of Cancer

NRF2 and the Hallmarks of Cancer

Potential Applications of NRF2 Modulators in Cancer Therapy

The Role of Nrf2 Activity in Cancer Development and Progression

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