The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression

Crosas‐Molist, Eva; Bertrán, Esther; Sancho, Patricia; López-Luque, Judit; Fernando, Joan; Sánchez, Aránzazu; Fernández, Margarita; Navarro, Estanis; Fabregat, Isabel

doi:10.1016/j.freeradbiomed.2014.01.040

Cited by 83 publications

(99 citation statements)

References 32 publications

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“…Inhibition of NOX1 gene expression with small interfering RNA in human colon cancer cells decreased tumor growth and angiogenesis markers in vivo 27. NOX4 knockdown caused increased cell proliferation in both human HCC cells and human and mouse hepatocytes, suggesting that NOX4 plays a negative role in liver cell proliferation, which is consistent with the result of this study 28. Lu et al 12.…”

Section: Discussionsupporting

confidence: 91%

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

Paik

Yang

et al. 2016

Gut and Liver

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Background/AimsNicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated reactive oxygen species contribute to various liver diseases, including hepatocellular carcinoma (HCC). Uncertainties remain regarding the prognostic relevance of NOX1 and NOX4 protein expression in HCC.MethodsNOX1 and NOX4 protein expression was examined by using immunohistochemistry in tumor tissue from 227 HCC patients who underwent hepatectomy.ResultsHigh immunoreactivity for NOX1 was observed in 197 (86.8%) of the 227 HCC cases and low immunoreactivity for NOX4 in 112 (49.3%). NOX1 and NOX4 proteins had opposite prognostic effects. High NOX1 expression was an independent predictor of both shorter recurrence-free survival (RFS) (p<0.01) and shorter overall survival (OS) (p=0.01). Low NOX4 expression was an independent predictor of both shorter RFS (p<0.01) and shorter OS (p=0.01). Subgroup analysis showed that, among patients with normal α-fetoprotein levels, patients with tumor size ≤5.0 cm and patients in Barcelona Clinic Liver Cancer stage A, high NOX1 expression had unfavorable effects on RFS, whereas low NOX4 expression had unfavorable effects on both RFS and OS.ConclusionsThese findings demonstrated that NOX1 and NOX4 protein expression had opposite prognostic effects for HCC patients. Moreover, both proteins had prognostic value in HCC patients with normal α-fetoprotein levels or with early-stage HCC.

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Section: Discussionsupporting

confidence: 91%

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

Paik

Yang

et al. 2016

Gut and Liver

View full text Add to dashboard Cite

show abstract

“…Along these lines, NOX4 silencing in human liver tumor cells as well as in untransformed human and mouse liver cells resulted in enhanced proliferation and tumor formation in xenograft experiments (54). However, similar to the findings we have reported here, NOX4 seems to play a contributing role for proliferation, migration and/or apoptosis resistance in glioma, pancreatic cancer, and melanoma cells (55)(56)(57).…”

Section: Discussionsupporting

confidence: 86%

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

et al. 2015

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Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.

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“…Reactive oxygen species, nitrogen and lipid peroxide should not be seen only as a byproduct of oxidative processes in the cell. They are important regulator components in biological systems, mediating signaling (Crosas-Molist et al, 2014), providing reliable maintenance of cellular components, supporting the redox-state in the cells (Niforou et al, 2014) and regulating the function of the immune system (McCarthy et al, 2013). Therefore, the products of overoxidation provide systemic regulation of metabolic processes along with hormones and other biologically active compounds and can be considered as one of the systemic factors forming an epigenotype.…”

Section: Enzymesmentioning

confidence: 99%

Thermogenesis and longevity in mammals. Thyroxin model of accelerated aging

Божков

Nikitchenko

2014

Experimental Gerontology

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The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression

Cited by 83 publications

References 32 publications

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

Thermogenesis and longevity in mammals. Thyroxin model of accelerated aging

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