Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Yamaguchi, Yasushi; Shao, Zhifei; Sharif, Shadi; Du, Xiao Yan; Myles, Timothy; Merchant, Milton; Harsh, Griffith R.; Glantz, Michael; Recht, Lawrence D.; Morser, John; Leung, Lawrence L.K.

doi:10.1074/jbc.m112.362954

Cited by 54 publications

(55 citation statements)

References 57 publications

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“…Therefore, the median CSF OPN level of our MS patients may differ to OPN levels reported by others. For GBM, high-level OPN expression has been demonstrated by immunohistochemistry, and relatively high OPN levels in CSF of GBM patients were reported in one study [34], which is in contrast to our findings. Methodological differences as well as differences in patients' characteristics and pre-treatment might be explanations for the difference to our GBM samples.…”

Section: Discussioncontrasting

confidence: 99%

Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

et al. 2016

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Central nervous system lymphoma (CNSL) is diagnostically challenging. The identification of reliable and easy to measure biomarkers is desirable to facilitate diagnosis. Here, we evaluated the value of cerebrospinal fluid (CSF) osteopontin (OPN) as a diagnostic biomarker for CNSL. OPN concentrations in CSF from 37 patients with CNSL (29 with primary CNSL and 8 with secondary CNS involvement of systemic lymphoma) and 36 controls [6 patients with inflammatory CNS disease other than multiple sclerosis (MS), 8 with MS, 9 with glioblastoma (GBM) and 13 healthy controls] were determined using an enzyme-linked immunosorbent assay. Non-parametric tests and receiver operating characteristic (ROC) curves were performed for determination of diagnostic accuracy. Median CSF OPN level in all CNSL patients was 620 ng/mL and higher than in patients with inflammatory CNS disease (356 ng/mL); P < .05, MS (163 ng/mL); P < .01, GBM (41 ng/mL); P < .01, or healthy controls (319 ng/mL); P < .01. The area under the ROC curve was 0.865 [95 % confidence interval (CI) 0.745-0.985] for differentiating CNSL and patients with inflammatory CNS disease; 0.956 (95 % CI 0.898-1.000) for CNSL and MS patients; 0.988 (95 % CI 0.964-1.000) for CNSL and GBM patients, and 0.915 (95 % CI 0.834-0.996) for CNSL patients and healthy controls. In multivariate analysis, high CSF OPN level was associated with shorter progression-free (HR 1.61, 95 % CI 1.13-2.31; P = .009) and overall survival (HR 1.52, 95 % CI 1.04-2.21; P = .029). CSF OPN is a potential biomarker in CNSL.

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Section: Discussioncontrasting

confidence: 99%

Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

et al. 2016

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“…It is interesting that thrombin cleavage of OPN, leading to the generation of OPN-R and its subsequent cleavage by CPB2 to OPN-L, has been previously shown to modulate cell adhesion in Jurkat cells (12), cultured synoviocytes (2,29), and some glioblastoma cell lines (11). These effects are mediated by the exposure of the SVVYGLR sequence in OPN-R and the subsequent removal of the C-terminal Arg 168 in OPN-L. Elevated OPN-R and OPN-L levels have been found in inflammatory diseases (29).…”

Section: Discussionmentioning

confidence: 99%

“…Adjacent to this RGD domain is a thrombin cleavage site at Arg 168 2Ser 169 . Thrombin cleavage of fulllength OPN (OPN-FL) leads to OPN-Arg (OPN-R), with a newly exposed C-terminal sequence, 162 SVVYGLR 168 , that binds to ␣4␤1 and ␣9␤1 integrins, allowing RGD-independent cell adhesion (8 -10) and a survival advantage to cells (11). Carboxypeptidase N (CPN) or B2 (CPB2) can remove Arg 168 from OPN-R, converting it to OPN-Leu (OPN-L), inactivating the binding site for integrin ␣ 9 ␤ 1 (12).…”

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confidence: 99%

Thrombin Cleavage of Osteopontin Disrupts a Pro-chemotactic Sequence for Dendritic Cells, Which Is Compensated by the Release of Its Pro-chemotactic C-terminal Fragment

Shao

Morser

Leung

2014

Journal of Biological Chemistry

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“…In brain tumors, inhibition of OPN reduces the clonogenic survival in glioma cell lines. Increased plasma OPN has been reported in malignant glioma patients and is associated with poor survival [13]. OPN is associated with neutrophil and macrophage infiltration in glioblastoma [14].…”

Section: Introductionmentioning

confidence: 99%

Polymorphism -433 C>T of the Osteopontin Gene is Associated with the Susceptibility to Develop Gliomas and their Prognosis in a Chinese Cohort

Shen

Chen²,

Hou

et al. 2014

Cell Physiol Biochem

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Aim: To investigate role of the Osteopontin (OPN) genetic polymorphisms in the susceptibility to gliomas and their prognosis. Methods: A total of 248 Chinese glioma patients and 281 age and sex matched healthy controls were recruited. The genetic polymorphisms at three loci, namely, -156 GG>G, -443 C>T and -66T>G, were determined. The log-rank test and Kaplan- Meier analysis were introduced to assess the effect of OPN gene polymorphisms on patient survival. Results: We found that the genotype frequencies of OPN -443 C>T polymorphism were significantly different between glioma patients and controls. Multivariable analyses showed a higher risk for gliomas in -443 CC genotype carriers compared to -443TT carriers (P<0.001). In addition, we also found the OPN -443 C>T polymorphism was closely related to the gliomas' tumor grade. The -443 C>T polymorphism also affected the tumor OPN expression level, but not the serum OPN level. More importantly, the -443 C>T polymorphism was significantly associated with the prognosis of these patients regardless of their treatment status. The patients with -443CC genotype had a poorer prognosis than those with -443TT and -443CT genotypes. In contrast, the -156 G>GG and -66T>G polymorphisms were not associated with risk, clinical characteristics, or prognosis of gliomas. Conclusion: This study suggests that the -443C>T gene polymorphisms may be used as a molecular marker for glioma occurrence and clinical outcome in glioma patients. © 2014 S. Karger AG, Basel

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Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Cited by 54 publications

References 57 publications

Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

Thrombin Cleavage of Osteopontin Disrupts a Pro-chemotactic Sequence for Dendritic Cells, Which Is Compensated by the Release of Its Pro-chemotactic C-terminal Fragment

Polymorphism -433 C>T of the Osteopontin Gene is Associated with the Susceptibility to Develop Gliomas and their Prognosis in a Chinese Cohort

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