Dual Roles of Oxidative Stress in Metal Carcinogenesis

Xu, Jie; Wise, James T.F.; Wang, Lei; Schumann, Kortney; Zhang, Zhuo; Shi, Xianglin

doi:10.1615/jenvironpatholtoxicoloncol.2017025229

Cited by 62 publications

(45 citation statements)

References 199 publications

(254 reference statements)

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“…High nuclear NRF1 and NRF2 protein expression may also predict a dismal outcome in patients before nodal or distant metastases occur, respectively. Thus, it is plausible that even if these redox-regulating and stress-sensing transcription factors have a protective role against melanoma carcinogenesis, they can be exploited as tumor-progressing factors in the malignant phase, as suggested earlier in other tumor types [51]. Additionally, redoxmiRs miR-144, miR-212, and miR-510 appear to associate with aggressive melanoma features, and their possible prognostic value should be evaluated in larger cohorts.…”

Section: Discussionmentioning

confidence: 98%

NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and MicroRNAs

Hämäläinen

Teppo

Skarp

et al. 2019

Oxidative Medicine and Cellular Longevity

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The prognostic significance of the major redox regulator nuclear factor erythroid-2-related factor (NRF2) is recognized in many cancers, but the role of NRF1 is not generally well understood in cancer. Our aim was to investigate these redox transcription factors in conjunction with redox-related microRNAs in naevi and melanoma. We characterized the immunohistochemical expression of NRF1 and NRF2 in 99 naevi, 88 primary skin melanomas, and 67 lymph node metastases. In addition, NRF1 and NRF2 mRNA and miR-23B, miR-93, miR-144, miR-212, miR-340, miR-383, and miR-510 levels were analysed with real-time qPCR from 54 paraffin-embedded naevi and melanoma samples. The immunohistochemical expression of nuclear NRF1 decreased from benign to dysplastic naevi (p < 0.001) and to primary melanoma (p < 0.001) and from primary melanoma to metastatic lesions (p = 0.012). Also, NRF1 mRNA levels decreased from benign naevi to dysplastic naevi (p = 0.034). Similarly, immunopositivity of NRF2 decreased from benign to dysplastic naevi (p = 0.02) and to primary lesions (p = 0.018). NRF2 mRNA decreased from benign to dysplastic naevi and primary melanomas (p = 0.012). Analysis from the Gene Expression Omnibus datasets supported the mRNA findings. High nuclear immunohistochemical NRF1 expression in pigment cells associated with a worse survival (p = 0.048) in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 expression in pigment cells associated with a worse survival (p = 0.033) in patients with M0 disease at the time of diagnosis. In multivariate analysis, neither of these variables exceeded the prognostic power of Breslow. The levels of miR-144 and miR-212 associated positively with ulceration (p = 0.012 and p = 0.027, respectively) while miR-510 levels associated positively with lymph node metastases at the time of diagnosis (p = 0.004). Furthermore, the miRNAs correlated negatively with the immunohistochemical expression of NRF1 and NRF2 but positively with their respective mRNA. Together, this data sheds new light about NFE2L family factors in pigment tumors and suggests that these factors are worth for further explorations.

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Section: Discussionmentioning

confidence: 98%

NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and MicroRNAs

Hämäläinen

Teppo

Skarp

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…While carcinogenesis is a multiple step process, when discussing the known mechanisms of metal-induced carcinogenesis, we conceptually refer to two stages. In the first stage of cadmium-induced carcinogenesis (from normal cells to transformed cells), ROS play a major role in the malignant cells transformation of BEAS-2BR cells exposed to cadmium (Son et al ., 2012; Xu et al ., 2017). Inhibition of ROS using antioxidant [catalase (CAT) or superoxide dismutase (SOD)] is able to decrease cadmium-induced carcinogenesis (Son et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane

Wang

Mandal

Son

et al. 2018

Toxicology and Applied Pharmacology

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124

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Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remains to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α, which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment. As measured by anchorage-independent colony formation assay, cadmium induced malignant cell transformation. Inhibition of ROS by antioxidants inhibited transformation, showing that ROS were important in the mechanism of this process. The inflammatory microenvironment created by cadmium may also contribute to the mechanism of the transformation. Using tandem fluorescence protein mCherry-GFP-LC3 construct, the present study shows that cadmium-transformed cells had a property of autophagy deficiency, resulting in accumulation of autophagosomes and increased p62. This protein upregulated Nrf2, which also upregulated p62 through positive feed-back mechanism. Constitutive Nrf2 activation increased its downstream anti-apoptotic proteins, Bcl-2 and Bcl-xl, resulting in apoptosis resistance. In untransformed BEAS-2BR cells, sulforaphane, a natural compound, increased autophagy, activated Nrf2, and decreased ROS. In cadmium-transformed BEAS-2BR cells, sulforaphane restored autophagy, decreased Nrf2, and decreased apoptosis resistance. In untransformed cells, this sulforaphane induced inducible Nrf2 to decrease ROS and possibly malignant cell transformation. In cadmium-transformed cells, it decreased constitutive Nrf2 and reduced apoptosis resistance. The dual roles of sulforaphane make this natural compound a valuable agent for prevention against cadmium-induced carcinogenesis.

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“…The second stage is the progression from malignantly transformed cells into tumors (tumorigenesis). 30 We investigated whether xenograft tumor-derived cells have mitochondrial respiration changes. This would further provide evidence that the tumor microenvironments may drive some of the mitochondrial dysfunctions found in cancer cells reported in the literature.…”

Section: Resultsmentioning

confidence: 99%

Investigating the Role of Mitochondrial Respiratory Dysfunction during Hexavalent Chromium-Induced Lung Carcinogenesis

Wise¹,

Wang²,

Alstott³

et al. 2018

J Environ Pathol Toxicol Oncol

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Hexavalent chromium [Cr(VI)] is a lung carcinogen and its complete mechanism of action remains to be investigated. Metabolic reprogramming of key energy metabolism pathways (e.g., increased anaerobic glycolysis in the presence of oxygen or “Warburg effect,” dysregulated mitochondrial function, and lipogenesis) are important to cancer cell and tumor survival and growth. In our current understanding of Cr(VI)-induced carcinogenesis, the role for metabolic reprogramming remains unclear. In this study, we treated human lung epithelial cells (BEAS-2B) with Cr(VI) for 6 months and obtained malignantly transformed cells from an isolated colony grown in soft agar. We also used Cr(VI)-transformed cells from two other human lung cell lines (BEP2D and WTHBF-6 cells). Overall, we found that all the Cr(VI)-transformed cells had no changes in their mitochondrial respiratory functions (measured by the Seahorse Analyzer) compared with passaged-matched control cells. Using a xenograft tumor growth model, we generated tumors from these transformed cells in Nude mice. Using cells obtained from the xenograft tumor tissues, we observed that these cells had decreased maximal mitochondrial respiration, spare respiratory capacity, and coupling efficiency. These results provide evidence that, although mitochondrial dysfunction does not occur during Cr(VI)-induced transformation of lung cells, it does occur during tumor development.

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Dual Roles of Oxidative Stress in Metal Carcinogenesis

Cited by 62 publications

References 199 publications

NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and MicroRNAs

NRF1 and NRF2 mRNA and Protein Expression Decrease Early during Melanoma Carcinogenesis: An Insight into Survival and MicroRNAs

Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane

Investigating the Role of Mitochondrial Respiratory Dysfunction during Hexavalent Chromium-Induced Lung Carcinogenesis

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