Expression of hypoxia-inducible factor-1α and its relationship to tumour angiogenesis and cell proliferation in cartilage tumours

Kubo, Toru; Sugita, Takahisa; Shimose, Shoji; Matsuo, Tomohiro; Arihiro, Koji; Ochi, Masami

doi:10.1302/0301-620x.90b3.19806

Cited by 44 publications

(36 citation statements)

References 19 publications

(22 reference statements)

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“…MRP functions as a transporter of GSH-X complexes and mediates the accumulation and excretion of drugs in cytoplasmic vesicles (4). HIF-1α plays essential roles in the regulation of MDR1 and MRP, and may be induced in the hypoxic microenvironment of cancers (9). In the present study, we found that hypoxia increased the resistance of A549/CDDP cells to cisplatin and increased the expression of HIF-1α, MDR1 and MRP.…”

Section: Discussionsupporting

confidence: 66%

Hypoxia-induced increases in A549/CDDP cell drug resistance are reversed by RNA interference of HIF-1α expression

Lee

Chen

et al. 2011

Mol Med Report

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Abstract. This study aimed to investigate the effects of knocking down hypoxia-inducible factor-1α (HIF-1α) through RNA interference on hypoxia-induced increases in drug resistance in A549/CDDP cells, and to study the underlying mechanisms. A small interfering RNA (siRNA) eukaryotic expression vector targeting HIF-1α was constructed and transfected into A549/CDDP cells treated with hypoxia. The mRNA and protein levels of HIF-1α, multidrug resistance-1 (MDR1), and multidrug resistance-associated protein (MRP) were determined by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. Cell viability following treatment with cisplatin was determined by MTT assay. Hypoxia increased the resistance of A549/CDDP cells to cisplatin and this effect was reversed by the siRNA inhibition of HIF-1α expression. Expression of HIF-1α siRNA also downregulated HIF-1α, MDR1 and MRP mRNA, and protein expression in A549/CDDP cells treated with hypoxia (p<0.05). Hypoxia-induced resistance of A549/CDDP cells to cisplatin is reversed by the siRNA inhibition of HIF-1α expression. This effect may be mediated by a decreased expression of MDR1 and MRP.

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Section: Discussionsupporting

confidence: 66%

Hypoxia-induced increases in A549/CDDP cell drug resistance are reversed by RNA interference of HIF-1α expression

Lee

Chen

et al. 2011

Mol Med Report

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“…Recently, Thienpont and colleagues reported that tumour hypoxia causes DNA hypermethylation and loss of 5hmC by reducing TET activity [57]. Interestingly, cartilage tissue and chondrosarcomas are known to have a hypoxic microenvironment [58, 59]; [60]; [61]. They also demonstrated a large overlap between genes hypermethylated in hypoxic versus IDH1 mutant glioblastomas [57].…”

Section: Discussionmentioning

confidence: 99%

IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas

Cleven

Suijker

Agrogiannis³

et al. 2017

Clin Sarcoma Res

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BackgroundMutations in isocitrate dehydrogenase (IDH)1 or -2 are found in ~50% of conventional central chondrosarcomas and in up to 87% of their assumed benign precursors enchondromas. The mutant enzyme acquires the activity to convert α-ketoglutarate into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which competitively inhibits α-ketoglutarate dependent enzymes such as histone- and DNA demethylases.MethodsWe therefore evaluated the effect of IDH1 or -2 mutations on histone modifications (H3K4me3, H3K9me3 and H3K27me3), chromatin remodeler ATRX expression, DNA modifications (5-hmC and 5-mC), and TET1 subcellular localization in a genotyped cohort (IDH, succinate dehydrogenase (SDH) and fumarate hydratase (FH)) of enchondromas and central chondrosarcomas (n = 101) using immunohistochemistry.Results IDH1 or -2 mutations were found in 60.8% of the central cartilaginous tumours, while mutations in FH and SDH were absent. The mutation status did not correlate with outcome. Chondrosarcomas are strongly positive for the histone modifications H3K4me3, H3K9me3 and H3K27me3, which was independent of the IDH1 or -2 mutation status. Two out of 36 chondrosarcomas (5.6%) show complete loss of ATRX. Levels of 5-hmC and 5-mC are highly variable in central cartilaginous tumours and are not associated with mutation status. In tumours with loss of 5-hmC, expression of TET1 was more prominent in the cytoplasm than the nucleus (p = 0.0001).ConclusionsIn summary, in central chondrosarcoma IDH1 or -2 mutations do not affect immunohistochemical levels of 5-hmC, 5mC, trimethylation of H3K4, -K9 and K27 and outcome, as compared to wildtype.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-017-0074-6) contains supplementary material, which is available to authorized users.

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“…As the cell type directly in contact with the blood, endothelial cells must adapt to changing conditions within the blood vessels and synthesize regulators of leukocyte and vascular smooth muscle cell behavior. Medical conditions, such as atherosclerosis, varicose veins, pulmonary hypertension, and tumor angiogenesis, may induce vascular hypoxia (Eyries et al, 2008;Han et al, 2008;Kubo et al, 2008;Osada-Oka et al, 2008a;Rankin et al, 2008), and the molecular aspects of hypoxia have been studied in order to explain the pathology underlying these diseases; however, many questions remain.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia induces Wee1 expression and attenuates hydrogen peroxide-induced endothelial damage in MS1 cells

Hong

Kim

et al. 2011

Exp Mol Med

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Abbreviations: cdc2, cell division cycle 2; cdk1, cycle dependent kinase 1; HIF-1α, hypoxia inducible factor-1α; Hsp, heat shock protein AbstractIn an oxygen-depleted environment, endothelial cells initiate an adaptive pattern of synthesis, which may enable them to survive hypoxic crises. Using high-resolution two-dimensional gel electrophoresis in conjunction with mass spectroscopy, we obtained a 24 differential display of proteins in the pancreatic endothelial cell line, MS-1, at four time points following induction of hypoxia. The induction of Wee1 under hypoxia was confirmed both at the mRNA and protein levels. The phosphorylation of cell division cycle 2, which is downstream of Wee1, was also increased after hypoxic exposure. In addition, pre-exposure to hypoxia attenuated a decrease in hydrogen peroxide-induced cell number. The induction of bax (a pro-apoptotic protein) and reduction of bcl (an anti-apoptotic protein) after hypoxia stimulus were also attenuated by hypoxic pre-exposure. Moreover, hydrogen peroxide-induced morphologic damage did not appear in the wild-type Wee1-expressing cells. Taken together, our results suggest that Wee1 may have important role in hypoxia-induced pathophysiological situations in endothelial cells.

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Expression of hypoxia-inducible factor-1α and its relationship to tumour angiogenesis and cell proliferation in cartilage tumours

Cited by 44 publications

References 19 publications

Hypoxia-induced increases in A549/CDDP cell drug resistance are reversed by RNA interference of HIF-1α expression

Hypoxia-induced increases in A549/CDDP cell drug resistance are reversed by RNA interference of HIF-1α expression

IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas

Hypoxia induces Wee1 expression and attenuates hydrogen peroxide-induced endothelial damage in MS1 cells

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