Expression pattern of osteopontin splice variants and its functions on cell apoptosis and invasion in glioma cells

Yan, Wei; Qian, Chunfa; Zhao, Peng; Zhang, Junxia; Shi, Lei; Qian, Jin; Liu, Ning; Fu, Zhen F.; Kang, Chunsheng; Pu, Peiyu; You, Yongping

doi:10.1093/neuonc/noq006

Cited by 51 publications

(54 citation statements)

References 25 publications

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“…This discovery appears to be in contrast to previous reports. For example, in malignant gliomas, OPN siRNA induced clear upregulation of Bax expression, downregulation of Bcl-2, Bcl-xL (25). Our findings are based on large cohort of HCC patients.…”

Section: Discussionsupporting

confidence: 48%

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

et al. 2013

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Abstract. Osteopontin (OPN) may facilitate tumorigenesis and metastasis through prevention of tumor cells from apoptosis. Although previous studies have suggested involvement of enhanced Bcl-2 protein family expression, the role of OPN together with Bcl-2 in hepatocellular carcinoma (HCC) remains unknown. In this study, we used western blotting to detect the OPN and Bcl-2 expression levels in cell lines with different OPN backgrounds and HCC tissues, and tumor tissue microarrays to examine OPN and Bcl-2 expression levels in 454 HCC cases. The Kaplan-Meier method and log-rank test were applied to investigate the predictive values of OPN and Bcl-2 in HCC patients. In vitro assays indicated that OPN expression increased concordantly with increasing metastatic potential in MHCC97-H, MHCC97-L, HepG2 and SMMC-7721 cell lines by western blotting, whereas Bcl-2 expression declined. In addition, Bcl-2 was highly upregulated in OPN knockdown MHCC97-H cell lines. Furthermore, in HCC tissues, it was confirmed that OPN levels were also significantly higher in recurrent tumor tissues compared to non-recurrent tissues by western blotting (p<0.001), whereas the contrary occurred in Bcl-2 (p=0.046). Using immunohistochemistry analysis, patients with higher OPN levels had significantly shorter median survival time and recurrence time compared to the lower ones, although the opposite occurred in Bcl-2 levels. Of note, when OPN and Bcl-2 were combined, we found that the co-index of OPN/Bcl-2 was an independent prognostic factor for both overall survival (p<0.001) and time to recurrence (p<0.001). Our findings demonstrate that OPN/Bcl-2 expression is a promising independent predictor of recurrence and survival in HCC. Additionally, Bcl-2 levels may be regulated by OPN in the HCC microenvironment.

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Section: Discussionsupporting

confidence: 48%

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

et al. 2013

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“…OPN-c, which lacks exon 4, has been reported to be expressed selectively in tumor tissues and correlated with tumor grade (52)(53)(54)(55)(56). Whereas OPN-a aggregates and enhances cell adhesion and therefore attenuates dissemination of tumor cells, OPN-c supports tumor invasion because of its lack of aggregation (52).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin Undergoes Polymerization in Vivo and Gains Chemotactic Activity for Neutrophils Mediated by Integrin α9β1

Nishimichi

Hayashita-Kinoh

Chen

et al. 2011

Journal of Biological Chemistry

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Osteopontin (OPN) is an integrin-binding inflammatory cytokine that undergoes polymerization catalyzed by transglutaminase 2. We have previously reported that polymeric OPN (polyOPN), but not unpolymerized OPN (OPN*), attracts neutrophils in vitro by presenting an acquired binding site for integrin ␣9␤1. Among many in vitro substrates for transglutaminase 2, only a few have evidence for in vivo polymerization and concomitant function. Although polyOPN has been identified in bone and aorta, the in vivo functional significance of polyOPN is unknown. To determine whether OPN polymerization contributes to neutrophil recruitment in vivo, we injected OPN* into the peritoneal space of mice. Polymeric OPN was detected by immunoblotting in the peritoneal wash of mice injected with OPN*, and both intraperitoneal and plasma OPN* levels were higher in mice injected with a polymerization-incompetent mutant, confirming that OPN* polymerizes in vivo. OPN* injection induced neutrophil accumulation, which was significantly less following injection of a mutant OPN that was incapable of polymerization. The importance of in vivo polymerization was further confirmed with cystamine, a transglutaminase inhibitor, which blocked the polymerization and attenuated OPN*-mediated neutrophil recruitment. The thrombin-cleaved N-terminal fragment of OPN, another ligand for ␣9␤1, was not responsible for neutrophil accumulation because a thrombin cleavage-incompetent mutant recruited similar numbers of neutrophils as wild type OPN*. Neutrophil accumulation in response to both wild type and thrombin cleavage-incompetent OPN* was reduced in mice lacking the integrin ␣9 subunit in leukocytes, indicating that ␣9␤1 is required for polymerization-induced recruitment. We have illustrated a physiological role of molecular polymerization by demonstrating acquired chemotactic properties for OPN. Osteopontin (OPN),3 an integrin-binding cytokine, plays critical roles in physiological and pathological processes, including inflammation, immunomodulation, tissue remodeling, fibrosis, mineralization (1), stem cell retention (2), and tumor metastasis (3). These functions are exerted through interactions with nine integrins and CD44 (4). OPN undergoes many types of post-translational modification, including phosphorylation (5), glycosylation, transglutamination (6), and proteolytic cleavage. Among these post-translational modifications, transglutamination (7) and thrombin-cleavage (8, 9) enhance interactions with integrins. Thrombin-cleaved N-terminal fragment of OPN (nOPN) has been found to play roles in rheumatoid arthritis (10, 11), autoimmune hepatitis (12), and stem cell retention in the bone marrow niche (2). Although OPN was found as a substrate for transglutaminase 2 (TG2; EC 2.3.2.13) earlier than thrombin, little is known about the functional role of the product of transglutamination, polymeric OPN. TG2 is a cross-linking enzyme that catalyzes isopeptide bonding between Gln and Lys residues (13) with specificity for amino acid sequences containing Gln (...

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“…6C). Because OPN is known to confer resistance to apoptosis (13,33), its effect on apoptosis was tested. Treatment with a STAT3 inhibitor, WP1066, induced significant apoptosis in U-87 MG cells (Fig.…”

Section: Opn Promoted U-87 Mg Cell Migration and Conferredmentioning

confidence: 99%

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

Yamaguchi

Shao

Sharif

et al. 2013

Journal of Biological Chemistry

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Background: Osteopontin (OPN) is highly expressed in glioblastoma (GBM) and possesses inflammatory activity modulated by proteolytic cleavage. Results: Cleaved OPN was increased in GBM and led to more adhesion of GBM cells. OPN conferred resistance to apoptosis in GBM cells. Conclusion: Increased osteopontin proteolysis increased GBM cell resistance to apoptosis. Significance: OPN cleavage links coagulation and inflammation providing a favorable niche for GBM development.

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Expression pattern of osteopontin splice variants and its functions on cell apoptosis and invasion in glioma cells

Cited by 51 publications

References 25 publications

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

Osteopontin Undergoes Polymerization in Vivo and Gains Chemotactic Activity for Neutrophils Mediated by Integrin α9β1

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

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