Pre- and post-translational regulation of osteopontin in cancer

Anborgh, Pieter H.; Mutrie, Jennifer C.; Tuck, Alan B.; Chambers, Ann F.

doi:10.1007/s12079-011-0130-6

Cited by 104 publications

(92 citation statements)

References 115 publications

(238 reference statements)

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“…In addition, a number of studies have demonstrated that OPN promoted tumor invasion and metastasis and regulated MMP-9 secretion (27)(28)(29)(30)(31). OPN was shown to combine with integrin αvβ3 and activate NF-κB (nuclear factor-κB) through the PI3K/Akt/IKK (κB kinase inhibitor) signaling pathway, increasing the secretion of urokinase-type plasmi nogen activator A (uPA) and promoting tumor invasion (32,33).…”

Section: Discussionmentioning

confidence: 99%

Role of osteopontin in the regulation of human bladder cancer proliferation and migration in T24 cells

Guo

Ding

et al. 2015

Molecular Medicine Reports

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Abstract. Osteopontin (OPN), a secreted acid glycoprotein with a variety of functions, promotes tumor proliferation, differentiation, invasion and metastasis. The aim of the current study was to investigate whether OPN may serve as a potential therapeutic target for human bladder cancer. RNA interference (RNAi) was performed to downregulate the expression of the OPN gene in T24 human bladder cancer cells. The mRNA and protein expression levels of OPN following RNAi were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. In addition, the cell cycle progression, apoptosis and proliferation were investigated using by flow cytometric analysis and MTT assay. The cell invasion ability was measured using a Matrigel transwell assay. The mRNA and protein expression levels of OPN were found to be significantly downregulated following RNAi. The proliferation and invasion of T24 cells were significantly inhibited in vitro. In conclusion, RNAi-targeting OPN may inhibit the proliferation, invasion and tumorigenicity of human bladder cancer cells. Therefore, OPN may serve as a potential therapeutic target for human bladder cancer. IntroductionBladder cancer is a common malignant tumors of the urinary system. In 2005, 63,210 new cases of bladder cancer were identified in America, of which 13,180 succumbed to the disease (1). With the development of an aging population, bladder cancer incidence is increasing year after year as incidence increases with age. Surgery is the main treatment method for bladder cancer; however, the 5-year average survival period remains poor (2). A previous study has demonstrated that the most important prognostic factors of bladder cancer include the pathological grading and staging (3). Long-term survival may be achieved through early detection and treatment. With the elucidation of the molecular biology of bladder cancer, gene therapy represents a novel method for the adjuvant treatment of the disease. Osteopontin (OPN) is a secreted acid glycoprotein with a variety of functions. OPN was initially isolated from the bone matrix and subsequently found in the tissues or cells of the placenta, decidua, smooth muscle and macrophages, as well as in various body fluids. In addition, OPN is an important component of the extracellular matrix. Previous studies have demonstrated that OPN is expressed in various tumor tissues and promotes tumor proliferation, differentiation, invasion and metastasis (4-9). A number of studies have shown that shorter survival time and poor prognosis are associated with high levels of OPN (10-13), while low plasma levels of OPN in patients are associated with good prognosis (14,15).RNA interference (RNAi) is a process of typical post-transcriptional regulation of gene expression, which is a conservative behavior in biological evolution, with resistance to virus invasion and maintaining the role of genetic stability (16,17,18). RNAi is induced by double-stranded RNA (dsRNA) gene silencing (18). When dsRNA is trans...

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Section: Discussionmentioning

confidence: 99%

Role of osteopontin in the regulation of human bladder cancer proliferation and migration in T24 cells

Guo

Ding

et al. 2015

Molecular Medicine Reports

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“…However, the N-terminal region adjacent to the signal peptide that is affected by splicing lacks any known ligand binding domains (64), although this region does include O-linked glycosylation and phosphorylation sites, and may also contain sites of interaction with the ECM (26). According to Anborgh et al, the exon labelled 'exon 5' in Figure 1 contains glutamine residues that undergo crosslinking by transglutaminase (31). This exon is absent in both OPN-c and OPN-4 variants, suggesting that these variants may be unable to form polymeric structures (Table 2 and Figure 1).…”

Section: Osteopontin Splice Variantsevidence For Association With Spementioning

confidence: 99%

“…While the predicted molecular weight of the proteins encoded by the five identified OPN splice variants ranges from 30.8 kDa (OPN-4) to 37.2 kDa (OPN-5; predicted molecular weights calculated using Expasy), the primary observed band in western blotting is typically around 70 kDa, and multiple bands ranging from 41 to 75 kDa are frequently observed (31). However, OPN undergoes extensive post-translational modification, with serine/threonine phosphorylation, glycosylation, tyrosine sulfation and cross-linking, and OPN is also a substrate for thrombin and matrix metalloproteinases (MMPs).…”

Section: Osteopontin Splice Variantsevidence For Association With Spementioning

confidence: 99%

“…There is a correspondingly large body of literature demonstrating the involvement of matricellular proteins in many and varied human disorders such as cancer, diabetes, cardiovascular disease and ocular disorders. For example, OPN is over-expressed in the stroma of a variety of cancers and increases malignancy and metastasis both in vivo and in vitro (31). High levels of SPARC expression in the tumour-stroma are similarly associated with disease progression in many cancers, including pancreatic cancer (4).…”

Section: Introductionmentioning

confidence: 99%

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Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

Viloria

Hill

2016

Biomolecular Concepts

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Matricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes. Alternative splicing is a precisely regulated process that can produce multiple isoforms with variable functions from a single gene. To date, the expression of alternate transcripts for the matricellular family has been reported for only a handful of genes. Here we analyse the evidence for alternative splicing across the matricellular family including the secreted protein acidic and rich in cysteine (SPARC), thrombospondin, tenascin and CCN families. We find that matricellular proteins have double the average number of splice variants per gene, and discuss the types of domain affected by splicing in matricellular proteins. We also review the clinical significance of alternative splicing for three specific matricellular proteins that have been relatively well characterised: osteopontin (OPN), tenascin-C (TNC) and periostin. Embracing the complexity of matricellular splice variants will be important for understanding the sometimes contradictory function of these powerful regulatory proteins, and for their effective clinical application as biomarkers and therapeutic targets.

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“…Moreover, OPN precursor mRNA undergoes alternative splicing leading to full-length OPN-a (i.e., consist of all exons), OPN-b (lacks exon 5) and OPN-c (lacks exon 4) as well [20]. The OPN splice variants are differentially expressed and may have functional heterogeneity in tumor specific manner [21] and recently are beginning to be studied in other diseases as calcific aortic valve disease [22], carotid atherosclerotic plaques [23] and systemic inflammatory conditions [24]. We have hypothesized that OPN isoforms and thrombin mRNA profile underlies the occurrence of pro-remodeling or pro-repair phenotype in endstage failing heart of different origin.…”

Section: Introductionmentioning

confidence: 99%

Myocardial expression analysis of osteopontin and its splice variants in patients affected by end-stage idiopathic or ischemic dilated cardiomyopathy

Cabiati

Svezia

Matteucci

et al. 2015

Vascular Pharmacology

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Osteopontin (OPN) is a phosphoglycoprotein of cardiac extracellular matrix and it is still poorly defined whether its expression changes in failing heart of different origin. The fulllength OPN-a and its isoforms (OPN-b, OPN-c) transcriptomic profile were evaluated in myocardium of patients with dilated or ischemic cardiomyopathy (DCM n = 8; LVEF% = 17.5±3; ICM n = 8; LVEF% = 19.5±5.2) and in auricle of valvular patients (VLP n = 5; LVEF %50), by Real-time PCR analysis. OPN-a and thrombin mRNA levels resulted significantly higher in DCM compared to ICM patients (DCM:31.3±7.4, ICM:2.7±1.1, p = 0.0002; DCM:19.1±4.9, ICM:5.4±2.2, p = 0.007, respectively). Although both genes' mRNA levels increased in patients with LVEF<50% (DCM+ICM) with respect to VLP with LVEF>50%, a significant increase in OPN (p = 0.0004) and thrombin (p = 0.001) expression was observed only in DCM. In addition, a correlation between OPN-a and thrombin was found in patients with LVEF<50% (r = 0.6; p = 0.003). The mRNA pattern was confirmed by OPN-a cardiac protein concentration (VLP:1.127±0.26; DCM:1.29±0.22; ICM:1.00±0.077 ng/ml). The OPN splice variants expression were detectable only in ICM (OPN-b: 0.357±0.273; OPN-c: 0.091±0.033) and not in DCM patients. A significant correlation was observed between collagen type I, evaluated by immunohistochemistry analysis, and both OPN-a mRNA expression (r = 0.87, p = 0.002) and OPN protein concentrations (r = 0.77, p = 0.016). Concluding, OPN-a and thrombin mRNA resulted dependent on the origin of heart failure while OPN-b and OPN-c highlighted a different expression for DCM and ICM patients, suggesting their correlation with different clinical-pathophysiological setting.

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Pre- and post-translational regulation of osteopontin in cancer

Cited by 104 publications

References 115 publications

Role of osteopontin in the regulation of human bladder cancer proliferation and migration in T24 cells

Role of osteopontin in the regulation of human bladder cancer proliferation and migration in T24 cells

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

Myocardial expression analysis of osteopontin and its splice variants in patients affected by end-stage idiopathic or ischemic dilated cardiomyopathy

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