The Possible Significance of the Ferrous Oxidase Activity of Ceruloplasmin in Normal Human Serum

Osaki, Shigemasa; Johnson, D. A. W.; Frieden, Earl

doi:10.1016/s0021-9258(18)96527-0

Cited by 629 publications

(98 citation statements)

References 18 publications

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“…The mRNA expression profiles of datasets GSE100666 and GSE68417 were downloaded from the GEO database, where GSE100666 consisted of three renal cell carcinoma samples and three normal tissue samples, and the raw data processed by Phalanx Human OneArray Ver. 6 (down-regulated genes) or log2FC > 2 (up-regulated genes) as differentially expressed genes. In the TCGA database, we assessed whether the two groups were statistically different by Wilcoxon test using the gene expression after normalization of tumor tissue and normal tissue.…”

Section: Rna-seq and Microarray Datamentioning

confidence: 99%

Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear‐cell renal cell carcinoma

Zhang

Chen

et al. 2021

FEBS Open Bio

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Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy. The pathogenesis of the disease is currently poorly understood, and the prognosis is poor. Therefore, in this study, we focused on exploring and identifying genes and signal transduction pathways that are closely related to ccRCC. Differentially expressed genes (DEGs) were analyzed using the renal cell oncogene expression profiles GSE100666 and GSE68417. DAVID evaluation of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used. We constructed a protein-protein interaction (PPI) network of DEGS using Cytoscape software and analyzed the submodules with the CytoHubba plugin. Finally, we performed western blot, immunohistochemistry and PCR validation by collecting tissues, and also utilized cells for in vitro functional analysis of ceruloplasmin (CP). In total, 202 DEGs (52 upregulated and 150 downregulated genes) were identified. Upregulated DEGs are significantly rich in angiogenesis, cell adhesion, and response to hypoxia, whereas downregulated DEGs are involved in intracellular pH regulation, excretion, coagulation, and chloride transmembrane transport. We selected the interactions of the top 20 hub genes provided by the PPI network, all of which are involved in important physiological pathways in vivo, such as complement and coagulation cascades. Tissue protein assays demonstrated that renal cancer highly expressed CP, while in vitro experiments showed that CP could promote the invasion of renal cancer cells. Our study suggests that ALB, C3, LOX, HRG, CXCR4, GPC3, SLC12A3, CP and CASR may be involved in the development

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Section: Rna-seq and Microarray Datamentioning

confidence: 99%

Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear‐cell renal cell carcinoma

Zhang

Chen

et al. 2021

FEBS Open Bio

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“…HIFs are transcription factors, which have been implicated as the major drivers of cancer progression and could be activated with various factors such as pH, nutrients and growth factors other than hypoxia [21]. The regulation of HIF degradation is dependent on iron, and CP stimulates iron efflux from the cell by releasing iron from iron export protein ferroportin via oxidation of ferrous (Fe 2+ ) into ferric (Fe 3+ ) [17,18]. Human normal bronchial epithelia (HBE) and lung cancer cell lines (CL1-0, CL1-5, H1299, H1563 and H1435) were used to test the expression of CP protein.…”

Section: Cp Affects Hif-2α Levels In Lung Cancer Cells Via Iron/phdsmentioning

confidence: 99%

“…Ceruloplasmin (CP) mediates several physiological functions such as copper transport, ferroxidase activity, superoxide dismutase activity and amine oxidase activity [16]. CP regulates the efflux of ferrous iron (Fe 2+ ) by releasing iron from export protein ferroportin via oxidation Fe 2+ into ferric iron (Fe 3+ ) [17,18]. Individuals with aceruloplasminemia, the absence of circulating serum CP, accumulate iron in vital organs such as the liver and basal ganglia, typically suffer from tissue injury and necrosis in their fourth to fifth decades of life [19].…”

Section: Introductionmentioning

confidence: 99%

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

Tsai

Chang

et al. 2020

IJMS

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For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF’s over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe2+ level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe2+ and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis.

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“…Hereditary caeruloplasmin deficiency has been described in patients since 1987 36–39. Caeruloplasmin is a copper containing serum protein with ferroxidase activity that oxidases ferrous iron (Fe II) to ferric iron (Fe III) 43. Because Fe III is the only iron form that can bind to apotransferrin and enter the bloodstream, caeruloplasmin deficiency would decrease recycling of iron from cell to plasma, resulting in cellular iron deposition 36…”

Section: Differential Diagnosismentioning

confidence: 99%

69‐Year‐old man with gait disturbance and parkinsonism

et al. 2001

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A 69-year-old man was referred for assessment of abnormal gait and posture. For 1 year, he had experienced progressive gait difficulty, characterized by festination and falling to either side. He also described feeling "glued to the ground" on occasion. He complained of tremor with action (particularly writing), hypophonia, and slight slurring of speech. He admitted to frequent inappropriate crying and laughter, urinary frequency and urgency, and severe constipation. He denied postural lightheadedness. His wife described slowness in responding to questions and mild memory difficulty. Six months prior to his initial assessment, he described an episode of sudden deterioration in his ambulation with incomplete recovery; other than this his symptoms had been slowly progressive. At the time of assessment he was unable to walk without assistance, and used a walker.Past medical history included "borderline" hypertension which was untreated, Type II diabetes mellitus diagnosed five years previously, hypothyroidism, and benign prostatic hypertrophy. He had smoked a pack of cigarettes daily for the previous 15 years. Current medications were glyburide, thyroxine, and vitamin B12 supplementation.On examination, his blood pressure was 170/100 lying and 155/100 standing. His general examination was otherwise unremarkable. On mental status testing, he was unable to give the date, nor name the clinic which he was visiting. He gave his date of birth as October 28, 1922 rather than October 31. He recalled one of three words at 5 minutes. He demonstrated normal limb praxis, but could not demonstrate how to suck through a straw or blow a kiss.His voice was hypophonic and speech slightly dysarthric. His face was expressionless, without eyelid retraction (see videotape). Jaw jerk was increased, and glabellar tap was positive. Horizontal eye movements were normal aside from saccadic smooth pursuit. Volitional vertical saccades were generated with some difficulty. Up-gaze was moderately diminished in range. Upward fast phases of optokinetic nystagmus (OKN) were absent and downward OKN fast phases were diminished. Cranial nerve examination was otherwise unremarkable.On motor examination, there was axial and bilateral limb rigidity. Bulk and power were normal. Rapid alternating movements were slow, irregular, and of low amplitude bilaterally, but without progressive decomposition. A mild tremor was present, greater with action than posture and absent at rest. Reflexes were pathologically brisk throughout, Hoffman's sign was present bilaterally and plantar responses were upgoing bilaterally. Sensory examination showed only mildly diminished vibration sensation in the distal lower extremities. His posture was markedly flexed, and gait was shuffling, but narrowbased. There was severe postural instability and he was unable to walk without assistance due to falling to either side. Writing was micrographic.A trial of Sinemet, up to 1,000 mg of levodopa daily, provided no benefit. A gradual progression of all symptoms ensued.

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The Possible Significance of the Ferrous Oxidase Activity of Ceruloplasmin in Normal Human Serum

Cited by 629 publications

References 18 publications

Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear‐cell renal cell carcinoma

Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear‐cell renal cell carcinoma

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

69‐Year‐old man with gait disturbance and parkinsonism

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