The Ratio of Hmox1/Nrf2 mRNA Level in the Tumor Tissue Is a Predictor of Distant Metastasis in Colorectal Cancer

Chang, Liang‐Che; Fan, Chung-Wei; Tseng, Wen-Ko; Chein, Hui-Ping; Hsieh, Tsan-Yu; Chen, Jim-Ray; Hwang, Cheng‐Cheng; Hua, Chung-Ching

doi:10.1155/2016/8143465

Cited by 19 publications

(16 citation statements)

References 40 publications

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“…Based on all these evidence, HMOX1 has been proposed as a target for cancer treatment ( 106 ), including its inducible repressor BACH1 ( 117 ), or its positive regulator Nrf2 ( 118 ).…”

Section: Hmox1 As a Cancer Targetmentioning

confidence: 99%

Heme Oxygenase-1 as a Modulator of Intestinal Inflammation Development and Progression

et al. 2018

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Heme Oxygenase 1 (HMOX1) is an enzyme that catalyzes the reaction that degrades the heme group contained in several important proteins, such as hemoglobin, myoglobin, and cytochrome p450. The enzymatic reaction catalyzed by HMOX1 generates Fe2+, biliverdin and CO. It has been shown that HMOX1 activity and the by-product CO can downmodulate the damaging immune response in several models of intestinal inflammation as a result of pharmacological induction of HMOX1 expression and the administration of non-toxic amounts of CO. Inflammatory Bowel Diseases, which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), are one of the most studied ailments associated to HMOX1 effects. However, microbiota imbalances and infections are also important factors influencing the occurrence of acute and chronic intestinal inflammation, where HMOX1 activity may play a major role. As part of this article we discuss the immune modulatory capacity of HMOX1 during IBD, as well during the infections and interactions with the microbiota that contribute to this inflammatory disease.

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“…Based on all these evidence, HMOX1 has been proposed as a target for cancer treatment ( 106 ), including its inducible repressor BACH1 ( 117 ), or its positive regulator Nrf2 ( 118 ).…”

Section: Hmox1 As a Cancer Targetmentioning

confidence: 99%

Heme Oxygenase-1 as a Modulator of Intestinal Inflammation Development and Progression

et al. 2018

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“…The activation of NRF2 in colorectal cancer has been shown to happen through at least two different mechanisms: hypermethylation of the KEAP1 promoter and deubiquitination of NRF2 [ 16 , 27 ]. However, the actual contribution of NRF2 to tumour development and therapeutic responses in colorectal cancer remains unclear, with conflicting data regarding NRF2 levels, the relevance of its localisation and correlation with prognosis [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Further, the use of potentially unspecific NRF2 antibodies [ 35 ] and the lack of antibody validation for in immunohistochemistry analyses call the results of some studies into question.…”

Section: Introductionmentioning

confidence: 99%

High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro

Torrente

Rezig

et al. 2020

Biomolecules

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Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established. Measuring the expression of surrogate genes for NRF2 activity in silico, in combination with validation in patients’ samples, we show that the NRF2 pathway is upregulated in colorectal tumours and that high levels of nuclear NRF2 correlate with a poor patient prognosis. These results highlight the need to overcome the protection provided by NRF2 and present an opportunity to selectively kill cancer cells with hyperactive NRF2. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2 and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 in colorectal cancer cells might present a vulnerability that could potentially be therapeutically exploited by using the Aurora kinase inhibitor AT9283.

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“…Redox stress has been mentioned as the first-hint in PD development [6,37]. To monitor redox imbalance, we chose Heme-oxygenase 1 ( Hmox1 ), noticed up-regulated in PD patients and considered a redox sensor [38,39,40,41], and sulfiredoxin1 ( Srnx1 ), an adaptive response to redox stress, potentially protecting DOPAn from ROS toxicity [38,42,43,44].…”

Section: Resultsmentioning

confidence: 99%

Earliest Mechanisms of Dopaminergic Neurons Sufferance in a Novel Slow Progressing Ex Vivo Model of Parkinson Disease in Rat Organotypic Cultures of Substantia Nigra

Ben

Bongiovanni

Tuniz

et al. 2019

IJMS

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The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia activation, apoptosis, a reduction in dopamine vesicle transporters, and the ubiquitination of misfolded protein clearance pathways were late (96 h, consequential) events. The work suggests inflammation and redox imbalance as simultaneous early mechanisms undergoing DOPAn sufferance, to be targeted for a causative treatment aimed to stop/delay PD.

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The Ratio of Hmox1/Nrf2 mRNA Level in the Tumor Tissue Is a Predictor of Distant Metastasis in Colorectal Cancer

Cited by 19 publications

References 40 publications

Heme Oxygenase-1 as a Modulator of Intestinal Inflammation Development and Progression

Heme Oxygenase-1 as a Modulator of Intestinal Inflammation Development and Progression

High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro

Earliest Mechanisms of Dopaminergic Neurons Sufferance in a Novel Slow Progressing Ex Vivo Model of Parkinson Disease in Rat Organotypic Cultures of Substantia Nigra

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