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Anti-apoptotic genes are synergistically activated in OVSAYO cells cultured under conditions of serum starvation and hypoxia.

ABSTRACT: The tumor microenvironment is generally hypoxic because of the limited oxygen supply from inefficient or insufficient vasculature. Hypoxic tumor tissues are also poorly supplied with serum components. We have previously demonstrated that expression of the FVII gene is induced in response to hypoxia in ovarian clear cell carcinoma (CCC) cells. This gene activation is synergistically enhanced when cells are simultaneously subjected to serum starvation, and is dependent on the transcription factor Sp1 directly associating with the FVII promoter. We have identified additional genes activated via a similar Sp1-dependent mechanism by conducting cDNA microarray analysis (GSE55565). ICAM1, which encodes intercellular adhesion molecule-1 (ICAM-1), is one such gene. ICAM-1 confers an anti-apoptotic effect upon CCC cells in vitro and promotes growth of CCC tumors. Here we describe the transcriptome analysis performed in our recently published study (Koizume et al., 2015). We further show that autonomous activation of the TNF?-NF?B axis is responsible for the synergistic activation of ICAM1 under hypoxic and serum starvation conditions. This study provides additional information as to how CCC cell survival can be facilitated under conditions of serum starvation and hypoxia.

SUBMITTER: Koizume S

PROVIDER: S-EPMC4583649 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Anti-apoptotic genes are synergistically activated in OVSAYO cells cultured under conditions of serum starvation and hypoxia.

Koizume Shiro S Miyagi Yohei Y

Genomics data 20150603

The tumor microenvironment is generally hypoxic because of the limited oxygen supply from inefficient or insufficient vasculature. Hypoxic tumor tissues are also poorly supplied with serum components. We have previously demonstrated that expression of the FVII gene is induced in response to hypoxia in ovarian clear cell carcinoma (CCC) cells. This gene activation is synergistically enhanced when cells are simultaneously subjected to serum starvation, and is dependent on the transcription factor ...[more]

PMID: 26484240

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Project description:Glycoproteins secreted by cells play essential roles in the regulation of extracellular activities. Secreted glycoproteins are often reflective of cellular status, and thus glycoproteins from easily accessible bodily fluids can serve as excellent biomarkers for disease detection. Cultured cells have been extensively employed as models in the research fields of biology and biomedicine, and global analysis of glycoproteins secreted from these cells provides insights into cellular activities and glycoprotein functions. However, comprehensive identification and quantification of secreted glycoproteins is a daunting task because of their low abundances compared with the high-abundance serum proteins required for cell growth and proliferation. Several studies employed serum-free media to analyze secreted proteins, but it has been shown that serum starvation, even for a short period of time, can alter protein secretion. To overcome these issues, we developed a method to globally characterize secreted glycoproteins and their N-glycosylation sites from cultured cells by combining selective enrichment of secreted glycoproteins with a boosting approach. The results demonstrated the importance of the boosting sample selection and the boosting-to-sample ratio for improving the coverage of secreted glycoproteins. The method was applied to globally quantify secreted glycoproteins from THP-1 monocytes and macrophages in response to lipopolysaccharides (LPS) and from Hep G2 cells treated with TGF-β without serum starvation. We found differentially secreted glycoproteins in these model systems that showed the cellular response to the immune activation or the epithelial-to-mesenchymal transition. Benefiting from the selective enrichment and the signal enhancement of low-abundance secreted glycoproteins, this method can be extensively applied to study secreted glycoproteins without serum starvation, which will provide a better understanding of protein secretion and cellular activity.

Project description:BackgroundContrast-induced nephropathy (CIN) is a major clinical problem associated with acute kidney injury during hospitalization. However, effective treatments for CIN are currently lacking. Mesenchymal stem cells (MSCs) have protective effects against kidney injury by suppressing inflammation and fibrosis. We previously showed that MSCs cultured in serum-free medium (SF-MSCs) enhance their anti-inflammatory and anti-fibrotic effects. However, whether SF-MSCs potentiate their anti-apoptotic effects is unknown. Here, we investigated the effects of SF-MSCs on a CIN mouse model.MethodsTo create CIN model mice, we removed right kidney at first. One week later, the left renal artery was clamped for 30 min to cause ischemia-reperfusion injury, and mice were injected with iohexol. Then the kidney received 10 Gy of irradiation, and MSCs or SF-MSCs were injected immediately. At 24 h post-injection, mice were sacrificed, and their blood and kidneys were collected to evaluate renal function, DNA damage, and apoptosis. In addition, apoptosis was induced in HEK-293 cells by irradiation and cells were treated with conditioned medium from MSCs or SF-MSCs.ResultsTreatment of CIN model mice with SF-MSCs markedly improved renal function compared with MSCs treatment. Cleaved caspase-3 levels and TUNEL-positive cell numbers were strongly suppressed in CIN model mice treated with SF-MSCs compared with the findings in those treated with MSCs. γH2AX levels, a chromosome damage marker, were reduced by MSCs and further reduced by SF-MSCs. In addition, cleaved caspase-3 in irradiated HEK-293 cells was more strongly suppressed by conditioned medium from SF-MSCs than by that from MSCs. Secretion of epidermal growth factor (EGF) was enhanced by culturing MSCs in serum-free medium. Knockdown of EGF by siRNA attenuated the inhibitory effects of SF-MSCs on CIN-induced renal dysfunction and tubular apoptosis.ConclusionsThese findings strongly suggest that SF-MSCs improve CIN in model mice by exerting anti-apoptotic effects in a paracrine manner. Thus, SF-MSCs represent a potential novel therapy for CIN.

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Anti-apoptotic genes are synergistically activated in OVSAYO cells cultured under conditions of serum starvation and hypoxia.

Publications

Anti-apoptotic genes are synergistically activated in OVSAYO cells cultured under conditions of serum starvation and hypoxia.

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