Creation of a lysine-deficient LIGHT mutant with the capacity for site-specific PEGylation and low affinity for a decoy receptor

Morishige, Tomohiro; Yoshioka, Yasuo; Inakura, Hiroshi; Tanabe, Aya; Yao, Xinglei; Tsunoda, Shin-ichi; Tsutsumi, Yasuo; Mukai, Yohei; Okada, Naoki; Nakagawa, Shinsaku

doi:10.1016/j.bbrc.2010.02.119

Cited by 10 publications

(6 citation statements)

References 26 publications

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“…The decoy receptor 3 (DcR3), locus on 20q13, is a member of the tumor necrosis factor receptor (TNFR) superfamily [1–4]. Previously, we have reported the overexpression of DcR3 mRNA and protein in sera or tissues of several human malignancies, including hepatocellular carcinoma, gastric carcinoma, and breast cancer [5–8].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma

Huang

Chen

Dang

et al. 2014

The Scientific World Journal

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Background. Overexpression of decoy receptor 3 (DcR3) have been reported in various classes of malignancies. However, its expression and clinicopathological contribution in gliomas has not been fully elucidated. Objective. To explore the expression and clinical significance of DcR3 protein in relation to tumor cell differentiation and proliferation in glioma cell lines and tissues. Methods. One hundred and twenty-five samples of glioma patients and 18 cases of normal brain tissues were recruited. The expression of DcR3 protein was detected using immunohistochemistry. Tumor differentiation was assessed by histologic characters and the status of glial fibrillary acidic protein (GFAP). Tumor cell labeling indexes (LIs) of Ki-67 and PCNA were also obtained. The relationship between the DcR3 level and clinicopathological features was investigated, including tumor differentiation, LIs, and survival. Meanwhile, the expression of DcR3 protein was also measured in the supernatants of 8 glioma cell lines and glioma cells freshly prepared from 8 human glioblastoma specimens by using western blot. Results. The level of DcR3 protein in gliomas was significantly higher than that in normal brain tissues (P < 0.01). DcR3 expression showed positive correlations with tumor pathological grade (r = 0.621, P < 0.01) and negative with GFAP expression (r = −0.489, P < 0.01). Furthermore, there were positive correlations between DcR3 expression and Ki-67, PCNA LIs (r = 0.529, P < 0.01; r = 0.556, P < 0.01). The survival in the DcR3 negative group was 50 ± 1.79 months, longer than that of the DcR3 positive group (48.36 ± 2.90), however, without significance (P = 0.149). Different levels of DcR3 could also be detected in the culturing supernatants of all the 8 glioma cell lines and glioma cells freshly obtained from 8 human glioblastoma specimens. Conclusions. The overexpression of DcR3 might play a crucial role in the tumorigenesis, differentiation, and proliferation of glioma.

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Section: Introductionmentioning

confidence: 99%

Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma

Huang

Chen

Dang

et al. 2014

The Scientific World Journal

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“…Thus, there is an urgent need to discover new biomarkers for the early detection and targeted molecular therapy. Tumor necrosis factor receptor super-family member 6b (TNFRSF6B, also termed as DcR3) locates on 20q13 [6][7][8][9] and we have previously reported the overexpression of TNFRSF6B mRNA and protein in sera or tissues of several human malignancies [10][11][12][13], including glioma [14]. We found that TNFRSF6B protein was significantly upregulated in glioma tissues, as well as in the supernatants of glioma cell lines and freshly primary cultured glioma cells.…”

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confidence: 77%

Effect of TNFRSF6B neutralization antibody on cell growth suppression and apoptosis induction in glioma cells

Ruan¹,

Huang²,

He³

et al. 2015

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Previously, we have reported that tumor necrosis factor receptor super-family member 6b (TNFRSF6B) is overexpressed in glioma tissues, as well as in the supernatant of cultured glioma cells. However, the function of TNFRSF6B in glioma remains unclarified. The aim of the study was to investigate the effect of anti-TNFRSF6B neutralization monoclonal antibody on the malignant phenotype of glioma cells in vitro. Three glioma cell lines U251MG, LN-308 and U87MG were treated with anti-TNFRSF6B antibody. Cell growth, cell cycle, apoptosis and relevant downstream signaling were detected further. We found that anti-TNFRSF6B antibody inhibited cell growth and induced apoptosis in time and dose-dependent manners in the glioma cells tested. Cell cycle was also arrested in G1/S-phase. Furthermore, anti-TNFRSF6B antibody downregulated the level of MMP-2, phospho-ERK1/2 and phospho-AKT. In conclusion, anti-TNFRSF6B treatment might be a critical targeted therapy strategy for gliomas due to its contribution to suppress cell growth and induce apoptosis. Key words: TNFRSF6B, glioma, proliferation, apoptosis, neutralization antibodyMalignant brain tumors are one of the most related causes of morbidity and mortality across a wide range of individuals [1]. Malignant gliomas, i.e., anaplastic astrocytoma and glioblastoma, are particularly aggressive [2]. They are the most frequent class of primary malignant brain tumors in China [3,4]. Many studies on this subject have produced advances in the understanding of glioma biology and pathogenesis and to the improvement of new agents for targeted molecular therapy [5]. However, the median survival of patients with newly diagnosed malignant glioma is only 12-14 months despite advanced therapeutic strategies. Thus, there is an urgent need to discover new biomarkers for the early detection and targeted molecular therapy. Tumor necrosis factor receptor super-family member 6b (TNFRSF6B, also termed as DcR3) locates on 20q13 [6-9] and we have previously reported the overexpression of TNFRSF6B mRNA and protein in sera or tissues of several human malignancies [10-13], including glioma [14]. We found that TNFRSF6B protein was significantly upregulated in glioma tissues, as well as in the supernatants of glioma cell lines and freshly primary cultured glioma cells. TNFRSF6B expression also had a positive correlation with tumor pathological grade. However, the exact role and pathomechanism of TNFRSF6B on the malignant phenotypes of glioma remains unclarified. Previously, our work showed that anti-TNFRSF6B neutralization monoclonal antibody could inhibit cell proliferation, reduce apoptosis and restrain migration ability in hepatocellular carcinoma HepG2 cells. Based on the overexpression of TNFRSF6B in glioma, we speculated that anti-TNFRSF6B neutralization monoclonal antibody could also affect the function of glioma cells. Therefore, in the present study, we treated glioma cells in vitro with anti-TNFRSF6B antibody and explored the effect of anti-TNFRSF6B antibody on the malignant phenotypes of glioma...

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“…Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor superfamily member 6B (TNFRSF6B), is located on chromosome 20q13.3 1–4. Some studies have published evidence on DcR3 overexpression in some malignant tumors such as colorectal carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic head carcinoma, renal cell carcinoma, and bladder transitional cell carcinoma 5,6.…”

Section: Introductionmentioning

confidence: 99%

Effect of DcR3-specific siRNA on cell growth suppression and apoptosis induction in glioma cells via affecting ERK and AKT

Zhang¹,

Huang

Leng³

et al. 2016

OTT

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BackgroundPreviously, we found that the expression of decoy receptor 3 (DcR3) in gliomas was significantly upregulated compared to normal brain tissues. However, the effect of DcR3-specific small interfering RNA (siRNA) on cell biological function of glioma cells remains incompletely understood.ObjectiveThe aim of this study was to explore the effect of DcR3 siRNA on cell growth and apoptosis of glioma cells and to investigate the potential downstream pathways affected by DcR3.MethodsDcR3-specific siRNA was transfected into three glioma cell lines (U251MG, LN-308, and U87MG) using combiMAGnetofection method. MTS tetrazolium assay and fluorimetric resorufin viability assay were used to assess the growth of glioma cells. Then, apoptosis was examined using the Hoechst 33342/propidium iodide double-staining assay and fluorescent caspase-3/7 assay. Meanwhile, Western blot was performed to explore the probable pathway by which DcR3-specific siRNA acts in glioma cells. Also, microarray dataset analysis was applied to analyze the potential function of DcR3 in glioma.ResultsThe DcR3-specific siRNA had a potent effect on cell growth and apoptosis of all three glioma cells tested, and the effects were time dependent. Among these three glioma cell lines, U251MG had the most significant effect with regard to growth inhibition and apoptosis induction. MTS assay showed that the proliferation rate at 72 and 96 hours after the transfection was 76.333%±5.131% (t=7.611, P=0.002) and 64.333%±5.859% (t=10.983, P<0.001), respectively. The viability rate of U251MG cells was 80.667%±2.309% (t=12.302, P<0.001) and 62.333%±2.082% (t=21.213, P<0.001) at 72 and 96 hours posttreatment, respectively. The caspase-3/7 activity of U251MG cells was 2.76 (t=−6.601, P=0.003) and 4.75 (t=−9.189, P=0.001) folds that of the mock control at 72 and 96 hours, respectively. The apoptosis rate was increased to 1.85 (t=−2.496, P=0.067) and 3.93 (t=−12.587, P<0.001) folds at 72 and 96 hours after transfection, respectively. Furthermore, the levels of phospho-ERK1/2 and phospho-AKT were significantly downregulated after DcR3 silencing.ConclusionThe DcR3-specific siRNA could efficiently inhibit growth and induce apoptosis of cells via affecting ERK and AKT. Hence, DcR3-specific siRNA treatment could act as a supplementary targeted therapy strategy for gliomas.

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Creation of a lysine-deficient LIGHT mutant with the capacity for site-specific PEGylation and low affinity for a decoy receptor

Cited by 10 publications

References 26 publications

Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma

Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma

Effect of TNFRSF6B neutralization antibody on cell growth suppression and apoptosis induction in glioma cells

Effect of DcR3-specific siRNA on cell growth suppression and apoptosis induction in glioma cells via affecting ERK and AKT

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