Abstract. Human osteopontin (OPN) is a glycosylated phosphoprotein which is expressed in a variety of tissues in the body. In recent years, accumulating evidence has indicated that the aberrant expression of OPN is closely associated with tumourigensis, progression and most prominently with metastasis in several tumour types. In this review, we present the current knowledge on the expression profiles of OPN and its main splice variants in human cancers, as well as the potential implications in patient outcome. We also discuss its putative clinical application as a cancer biomarker and as a therapeutic target. IntroductionOsteopontin (OPN) is a bone associated, extracellular matrix glycosylated phosphoprotein which is produced by several cell types, including osteoblasts, osteoclasts, immune cells, endothelial cells, epithelial cells and extra-osseous cells (skin, kidney and lung) (1-3). Due to differences in post-translational modification (PTM) (phosphorylation, glycosylation, sulfation and proteolysis) from different cellular sources, OPN has a molecular weight ranging from 41 to 75 kDa, which may have a cell type-specific structure and function (4-7). OPN plays a major role in various normal physiological processes, including bone remodelling, immune-regulation, inflammation and vascularisation (8,9). In addition, OPN has also been shown to be involved in carcinogenesis with multi-functional activities (10)(11)(12).OPN is involved in a series of biological functions through interactions with different integrins and CD44. Therefore, OPN is classified as a member of the ʻsmall integrin-binding ligand N-linked glycoproteins' (SIBLINGs) together with other molecules, including bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE) (13). Two critical integrin binding sequences of OPN have been identified: arginine-glycine-aspartic acid (RGD) and serine-valine-valinetyrosine-glutamate-leucine-arginine (SVVYGLR). OPN interacts mainly with various αv (particularly αvβ1, αvβ3, αvβ5) integrin receptors via the classical RGD sequence, and interacts with α9β1, α4β1, α4β7 via SVVYGLR (14-16). In addition, it also interacts with the CD44 splice variants, CD44v3, CD44v6 and CD44v7, via the C-terminal fragment calcium binding site (17)(18)(19)(20). These properties of OPN induce the activation of signal transduction pathways, leading to cell proliferation, adhesion, invasion and migration, which have been demonstrated by both in vitro and in vivo models (21-23). The binding of OPN to integrins and CD44 initiates a downstream signalling cascade via the PI3K/AKT signalling pathway leading to NF-κB mediated cell proliferation and survival (24)(25)(26). In additon, through the Ras/Raf/MEK/ERK signalling pathway, an OPN-integrin complex and subsequent induction of AP-1-dependent gene expression, urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) confer a metastatic phenotype on some cancer cell types (27)(28)(29...
Background: The clinical and prognostic value of programmed death-ligand 1, PD-L1, in glioblastoma remains controversial. The present study aimed to identify the expression of PD-L1 for its prognostic value in glioblastoma. Methods: A comprehensive literature search was performed using the PubMed and CNKI databases. The overall survival (OS) and disease-free survival (DFS) of GBM was analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for clinicopathological parameters. The statistical analysis was using RevMan 5.3 software. Results: The meta-analysis was performed by using total nine studies including 806 patients who had glioblastoma. The pooled results indicated that PD-L1 expression in tumor tissues was significantly related to a poor OS (HR = 1.63, 95%CI: 1.19-2.24, P = 0.003, random effects model) with heterogeneity (I 2 = 51%). In subgroup analyses, PD-L1 positivity was significantly associated with a worse OS for patients of American and Asian regions, but not for those of European regions. Moreover, PD-L1 expression implied a trend toward the mutation status of the IDH1 gene [coding the Isocitrate Dehydrogenase (NADP(+))-1 protein] (HR = 9.92, 95%CI: 1.85-53.08, P = 0.007, fixed effects model). However, the prediction overall survival (OS) of the patients showed that PD-L1 expression was independent from other clinicopathological features, such as gender and age. Conclusions: Our analyses indicated that high expression of PD-L1 in glioblastoma tumor tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma.
Background: Clinical treatment of non-small cell lung carcinoma (NSCLC) by cisplatin eventually results in drug resistance, which cancer stem cells and autophagy are believed to be involved in. In the present study, we aimed to explore the effect of autophagy-inhibited cancer stem cells in NSCLC. Methods: Cancer stem cells were identified by CD133 expression levels detected by immunochemistry, real-time polymerase chain reaction, western blot, and flow cytometry. Stemness was detected by sphere-forming assays of tumor cells. Autophagy was determined by LC3-II expression at mRNA and protein levels. The effect of chloroquine (CQ) on autophagy was detected by real-time polymerase chain reaction, western blot and sphere-forming assay in vitro, and tumor growth in male NOD/SCID mice. Results: Cisplatin (CDDP) treatment enhanced CD133+ cell ratios in clinical NSCLC specimens and NSCLC cell line A549. The CD133+ cells enriched by CDDP exhibited higher autophagy levels. Autophagy inhibition by CQ inhibited CD133+ stemness and promoted CDDP efficiency in A549 cells. In addition, the combination of CDDP and CQ treatment significantly inhibited autophagy levels and cancer stem cell proportions in vitro, and dramatically suppressed tumor growth compared with individual agents. Conclusion: Autophagy inhibition of cancer stem cells could promote the efficacy of cisplatin against NSCLC. The reviews of this paper are available via the supplemental material section.
OPN-a may represent a bone metastatic factor in human lung cancer, as well as a potential therapy target.
Objectives. Osteopontin (OPN) is overexpressed in breast cancers, while its clinical and prognostic significance remained unclear. This study aimed to assess the prognostic value of OPN, especially its splice variants, in breast cancers. Methods. Data were extracted from eligible studies concerning the OPN and OPN-c expression in breast cancer patients and were used to calculate the association between OPN/OPN-c and survival. Two reviewer teams independently screened the literatures according to the inclusion and exclusion criteria based on quality evaluation. Following the processes of data extraction, assessment, and transformation, meta-analysis was carried out via RevMan 5.3 software. Results. A total of ten studies involving 1,567 patients were included. The results demonstrated that high level OPN indicated a poor outcome in the OS (HR = 2.22, 95% CI: 1.23–4.00, and P = 0.008; random-effects model) with heterogeneity (I 2 = 62%) of breast cancer patients. High level OPN-c appeared to be more significantly associated with poor survival (HR = 2.14, 95% CI: 1.51–3.04, and P < 0.0001; fixed-effects model) with undetected heterogeneity (I 2 = 0%). Conclusions. Our analyses indicated that both OPN and OPN-c could be considered as prognostic markers for breast cancers. The high level of OPN-c was suggested to be more reliably associated with poor survival in breast cancer patients.
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