Function Of Periostin Research Articles

Periostin in Bone Biology.

Periostin is specifically expressed in periosteum that functions in bone modeling and remodeling and bone repair, and is sensitive to mechanical stress. Thus periostin has been expected for controlling these crucial systems in bone. The results from periostin deficient mice demonstrate that periostin acts on bone remodeling though detailed mechanisms are unknown. Recent findings have revealed that periostin is essential for bone repair. In this chapter, I introduce expression and function of periostin in bone.

The Structure of the Periostin Gene, Its Transcriptional Control and Alternative Splicing, and Protein Expression.

Although many studies have described the role of periostin in various diseases, the functions of periostin derived from alternative splicing and proteinase cleavage at its C-terminus remain unknown. Further experiments investigating the periostin structures that are relevant to diseases are essential for an in-depth understanding of their functions, which would accelerate their clinical applications by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress .

Periostin Functions as a Scaffold for Assembly of Extracellular Proteins.

Periostin is a secretory matricellular protein with a multi-domain structure that is composed of an amino-terminal EMI domain, a tandem repeat of four FAS 1 domains, and a carboxyl-terminal domain (CTD). Periostin has been suggested to function as a scaffold for assembly of several extracellular matrix proteins as well as its accessory proteins (Fig. 3.1, Table 3.1), which underlies highly sophisticated extracellular architectures. This scaffold function is likely due to periostin's multi-domain structure, in which the adjacent domains in periostin interact with different kinds of proteins, put these interacting proteins in close proximity, and promote intermolecular interactions between these proteins, leading to their assembly into a large complex. In this chapter, I introduce the proteins that interact with each of the adjacent domains in periostin, and discuss how the multi-domain structure of periostin functions as a scaffold for the assembly of the interacting proteins, and how it underlies construction of highly sophisticated extracellular architectures.

Periostin in Bone Regeneration.

Bone regeneration is an efficient regenerative process depending on the recruitment and activation of skeletal stem cells that allowcartilage and bone formation leading to fracture consolidation. Periosteum, the tissue located at the outer surface of bone is now recognized as an essential player in the bone repair process and contains skeletal stem cells with high regenerative potential. The matrix composition of the periosteum defines its roles in bone growth, in cortical bone modeling and remodeling in response to mechanical strain, and in bone repair. Periostinis a key extracellular matrix component of the periosteum involved in periosteum functions. In this chapter, we summarize the current knowledge on the bone regeneration process, the role of the periosteum and skeletal stem cells, and Periostin functions in this context. The matricellular protein Periostinhas several roles through all stages of bone repair: in the early days of repair during the initial activation of stem cells within periosteum, in the active phase of cartilage and bone deposition in the facture callus, and in the final phase of bone bridging and reconstitution of the stem cell pool within periosteum.

Periostin Reexpression in Heart Disease Contributes to Cardiac Interstitial Remodeling by Supporting the Cardiac Myofibroblast Phenotype.

Cardiac muscle (the myocardium) is a unique arrangement of atria and ventricles that are spatially and electrically separated by a fibrous border. The spirally-arranged myocytes in both left and right ventricles are tethered by the component molecules of the cardiac extracellular matrix (ECM), including fibrillar collagen types I and III. Loss of normal arrangement of the ECM with either too little (as is observed in acute myocardial infarction) or too much (cardiac fibrosis in chronic post-myocardial infarction) is the primary contributor to cardiac dysfunction and heart failure. Matricellular proteins exist as non-structural signaling moieties in the ECM, and in the context of cardiac hypertrophy and heart failure, secreted 90kDa periostin protein has attracted intense scrutiny during the past decade. Secreted periostin is now recognized for its important role in ECM development and maturation, as well as cellular adhesion. The novel mechanisms of periostin function include its role as a mediator of cell-to-matrix signaling, cell survival, and epithelial-mesenchymal transition (EMT). A number of recent studies have examined the hypothesis that periostin is a major contributor to ECM remodeling in the heart, and a number of very recent studies underscore its important role. This review examines recent developments in the mechanisms of periostin function in the normal heart and vasculature, and discusses recent advances which underpin its putative role in the development of cardiovascular disease. Periostin expression is very low at baseline in healthy tissues, but is re-expressed in damaged heart and in vessel walls after injury, in activated cardiac myofibroblasts and vascular smooth muscle cells, respectively. For this reason, periostin may be exploited for investigation of mechanisms of cardiac fibrosis , and we speculate that data generated from studies utilizing this approach may shed light on the timing for application of periostin-specific therapies to quell cardiac fibrosis and associated cardiac dysfunction.

Liver, Stroke, Rhinosinusitis.

In addition to main types of fibrosis, other types of fibrosis in incredible diseases have been reported. Among them, liver fibrosis, stroke, and rhinosinusitis are described as new cases of periostin action. To understand periostin function in a new area of fibrosis linked with inflammation, periostin can be used as a new tool to elucidate the mechanisms of unknown diseases.

Experimental Inhibition of Periostin Attenuates Kidney Fibrosis

Background: Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis. Methods: We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used. Results: Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, α-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-β signaling and the inflammatory and apoptotic pathways. Conclusion: Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression.

Periostin function in communication with extracellular matrices.

Periostin is a secretory protein with a multi-domain structure, comprising an amino-terminal cysteine-rich EMI domain, four internal FAS 1 domains, and a carboxyl-terminal hydrophilic domain. These adjacent domains bind to extracellular matrix proteins (type I collagen, fibronectin, tenascin-C, and laminin γ2), and BMP-1 that catalyzes crosslinking of type I collagen, and proteoglycans, which play a role in cell adhesion. The binding sites on periostin have been demonstrated to contribute to the mechanical strength of connective tissues, enhancing intermolecular interactions in close proximity and their assembly into extracellular matrix architectures, where periostin plays further essential roles in physiological maintenance and pathological progression. Furthermore, periostin also binds to Notch 1 and CCN3, which have functions in maintenance of stemness, thus opening up a new field of periostin action.

Functions of Periostin in dental tissues and its role in periodontal tissues' regeneration.

The goal of periodontal regenerative therapy is to predictably restore the tooth's supporting periodontal tissues and form a new connective tissue attachment of periodontal ligament (PDL) fibers and new alveolar bone. Periostin is a matricellular protein so named for its expression primarily in the periosteum and PDL of adult mice. Its biological functions have been widely studied in areas such as cardiovascular physiology and oncology. Despite being initially identified in the dental tissues and bone, investigations of Periostin functions in PDL and alveolar-bone-related physiopathology are less abundant. Recently, several studies have suggested that Periostin may be an important regulator of periodontal tissue formation. By promoting collagen fibrillogenesis and the migration of fibroblasts and osteoblasts, Periostin might play a pivotal part in regeneration of the PDL and alveolar bone following periodontal surgery. The aim of this article is to provide an extensive review of the implications of Periostin in periodontal tissue biology and its potential use in periodontal tissue regeneration.

Introductory review: periostin-gene and protein structure.

Although many studies have described the role of periostin in various diseases, the function of the periostin protein structures derived from alternative splicing and proteinase cleavage at the C-terminal remain unknown. Further experiments revealing the protein structures that are highly related to diseases are essential to understand the function of periostin in depth, which would accelerate its clinical application by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress.

Periostin suppresses in vivo invasiveness via PDK1/Akt/mTOR signaling pathway in a mouse orthotopic model of bladder cancer.

Periostin is an extracellular matrix protein involved in the regulation of intercellular adhesion. The present study investigated the in vivo tumor suppressor function of periostin in a mouse orthotopic model of bladder cancer. Retroviral vectors were used to transfect human bladder cancer UMUC-3 cell line with periostin. Bladders of nude mice that were transurethrally instilled with periostin-expressing UMUC-3 cells were revealed to weigh less compared with bladders instilled with vector control cells. In total, five (83.3%) of six vector control UMUC-3 bladder tumors exhibited histological evidence of muscle invasion. However, none of the five periostin-expressing UMUC-3 bladder tumors revealed muscle invasion. Thick edematous lesions were present in the submucosa of periostin-expressing UMUC-3 bladder tumors. The expression of periostin also suppressed in vitro cell invasiveness of UMUC-3 cells without affecting cellular proliferation. The level of phosphorylation of phosphoinositide-dependent kinase-1 (PDK1), protein kinase B (Akt) and S6 ribosomal protein, a downstream protein of mammalian target of rapamycin (mTOR) was decreased in periostin-expressing UMUC-3 cells compared with vector control cells. Treatment with 100 ng/ml recombinant human periostin protein also suppressed cell invasiveness and phosphorylation of PDK1, Akt and S6 in UMUC-3 cells, consistent with results using periostin-expressing UMUC-3 cells. Treatment with PDK1, Akt and mTOR inhibitors significantly suppressed UMUC-3 cell invasiveness. These results demonstrate that periostin suppresses in vivo and in vitro invasiveness of bladder cancer via the PDK1/Akt/mTOR signaling pathway. Periostin may be useful as a potent chemotherapeutic agent by suppressing bladder cancer invasiveness.

Clinical Significance of Periostin in Egyptian Asthmatic Patients

Abstract: Objective: Asthma is an inflammatory disease of the airways appropriate to pulmonary eosinophilia, airway hyperresponsiveness (AHR) and mucus overproduction. We now investigate the level of Periostin serum concentration in Egyptian asthmatic patients and define any correlation between periostin and Pulmonary Function Tests (PFT) Methods: 80 subjects were enrolled in the study: 20 control (11 male and 9 female), 28 atopic asthmatic patients (19 male and 9 female) and 32 non- atopic asthmatic patients (14 male and 18 female).Blood samples were obtained from the subjects for laboratory investigations which divided into two aliquots, First aliquot for whole blood used for complete blood count to determine blood eosinophil count by using Sysmex XP-300 and Second aliquot for serum used for estimation of Periostin, Transforming Growth Factor (TGF-β1) and Total Immunoglobulin (IgE) using enzyme-linked immunosorbent assays(ELISA).Results: Periostin concentrations were significantly higher in atopic and non- atopic groups (mean±SE; 6889±393.8 and 6212±348.8 pg/ml respectively) compared to control group (3053±446.5 pg/ml) at P < 0.05.TGF-β1 were significantly higher in atopic and non- atopic groups (mean±SE;75.83 ±1.53and 73.47±1.09 pg/ml respectively) compared to control group (51.26±2.65 pg/ml) at P < 0.05and IgE were significantly higher in atopic group (mean±SE;151.3±15.10IU /ml) compared to control group and non- atopic groups (52.47±3.045 and 48.51±1.827 IU /ml respectively) at P < 0.05.Periostin correlated negatively with PFT which Forced Vital Capacity (FVC), Forced Expiratory Volume1(FEV1) and Forced Expiratory Volume 1% (FEV1%).Conclusions: Serum Periostin is increased in Egyptian asthmatic (atopic and non- atopic) patients compared to control and Periostin correlated negatively with pulmonary function tests in asthmatic patients. Asthma is the most significant variable relates to high Periostin serum concentration.

Molecular characterization, tissue expression profile, and single nucleotide polymorphism analysis of the periostin gene in swine.

Periostin, also called osteoblast-specific factor 2, is an important regulator of bone, cardiac development, and wound healing. A recent study revealed that periostin plays an important role in tumor development and is upregulated in a wide variety of cancers. However, little is known about periostin in swine. Therefore, the cDNA sequence of the porcine periostin gene was obtained by rapid amplification of cDNA ends (RACE). One C/T single nucleotide polymorphism anchored in intron 9 was identified and genotyped by PCR-RFLP-HaeIII. In Daweizi, Shaziling, Ningxiang, Taoyuan, Wuzhishan, Landrace, and Yorkshire pigs, the C allele was dominant, while the T allele was dominant in the Duroc pig. Quantitative PCR analysis showed that the periostin gene was expressed in all examined tissues from 25-day-old Shaziling and Yorkshire piglets, with mRNA expression in the longissimus dorsi muscle being the highest in these two breeds, and that in the kidney and lungs being the lowest. There was a significant difference in periostin gene expression in the intestines, heart, and spleen (P < 0.05). These findings might contribute to our understanding of the function of periostin in swine.

Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin

Background/Aims: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC. Methods: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model. Results: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin-silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors. Conclusion: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.

Deletion of Periostin Protects Against Atherosclerosis in Mice by Altering Inflammation and Extracellular Matrix Remodeling.

Periostin is a secreted protein that can alter extracellular matrix remodeling in response to tissue injury. However, the functional role of periostin in the development of atherosclerotic plaques has yet to be described despite its observed induction in diseased vessels and presence in the serum. Hyperlipidemic, apolipoprotein E-null mice (ApoE(-/) (-)) were crossed with periostin (Postn(-/-)) gene-deleted mice and placed on a high-fat diet for 6 or 14 weeks to induce atherosclerosis. En face analysis of aortas showed significantly decreased lesion areas of ApoE(-/-) Postn(-/-) mice compared with ApoE(-/-) mice, as well as a reduced inflammatory response with less macrophage content. Moreover, diseased aortas from ApoE(-/-) Postn(-/-) mice displayed a disorganized extracellular matrix with less collagen cross linking and smaller fibrotic caps, as well as increased matrix metalloproteinase-2, metalloproteinase-13, and procollagen-lysine, 2-oxoglutarate 5-dioxygenase-1 mRNA expression. Furthermore, the loss of periostin was associated with a switch in vascular smooth muscle cells toward a more proliferative and synthetic phenotype. Mechanistically, the loss of periostin reduced macrophage recruitment by transforming growth factor-β in cellular migration assays. These are the first genetic data detailing the function of periostin as a regulator of atherosclerotic lesion formation and progression. The data suggest that periostin could be a therapeutic target for atherosclerotic plaque formation through modulation of the immune response and extracellular matrix remodeling.

Expression and pathological effects of periostin in human osteoarthritis cartilage.

BackgroundOsteoarthritis (OA) is one of the most common joint diseases in elderly people, however, the underlying mechanism of OA pathogenesis is not completely clear. Periostin, the extracellular protein, has been shown by cDNA array analysis to be highly expressed in OA, but its function is not fully understood. The purpose of this study was to examine the expression and function of periostin in human OA.MethodsHuman cartilage and synovia samples were used for the analysis of periostin expression and function. The human cartilage samples were obtained from the knees of patients undergoing total knee arthroplasty as OA samples and from the femoral bone head of patients with femoral neck fracture as control samples. Quantitative RT-PCR, ELISA, and immunohistochemistry were used for analysis of periostin expression in cartilage and synovia. Human primary chondrocytes isolated from control cartilage were stimulated by periostin, and the alteration of OA related gene expression was examined using quantitative RT-PCR. Immunocytochemistry of p65 was performed for the analysis of nuclear factor kappa B (NFκB) activation.ResultsThe periostin mRNA was significantly higher in OA cartilage than in control cartilage. Immunohistochemical analysis of periostin showed that the main positive signal was localized in chondrocytes and their periphery matrix near the erosive area, with less immunoreactivity in deeper zones. There was positive correlation between Mankin score and periostin immunoreactivity. The periostin expression was also detected in the fibrotic cartilage and tissue of subchondral bone. In cultured human chondrocytes, periostin induced the expression of interleukin (IL)-6, IL-8, matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, and nitric oxide synthase-2 (NOS2) in a dose- and time-dependent manner. The activation of NFκB signaling was recognized by the nuclear translocation of p65. Periostin-induced upregulation of these genes was suppressed by NFκB inactivation in chondrocytes.ConclusionPeriostin was upregulated in OA cartilage, and it may amplify inflammatory events and accelerate OA pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-015-0682-3) contains supplementary material, which is available to authorized users.

Elevated expression of periostin in diabetic cardiomyopathy and the effect of valsartan.

BackgroundPeriostin, an extracellular matrix protein, plays a significant role in adverse cardiac remodeling. However, no report has documented the function of periostin in left ventricular remodeling of streptozototin (STZ)-induced diabetic rats. The aim of the present study was to observe the expression of periostin in Wistar rat’s myocardium of diabetic cardiomyopathy (DCM) and the effect of valsartan on it.MethodsImmunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were used to determine the degree of expression and location of periostin, transforming growth factor (TGF)-β1, TGF-β1 type II receptor (TGF-β1 R II), and Type I and III collagens in the myocardium of STZ-induced diabetic rats.ResultsPeriostin, TGF-β1, TGF-β1 R II, and Type I and III collagens were significantly increased in the myocardium of diabetic rats compared with control group on both messenger ribonucleic acid and protein levels. In addition, diabetic rats treated with valsartan could have reduced expression of periostin and improved cardiac remodeling of DCM.ConclusionsPeriostin may play a crucial role in cardiac remodeling and myocardial interstitial fibrosis process of DCM and it could be one of the important mechanisms for valsartan to improve the ventricular remodeling of DCM.

Abstract B08: The role of periostin in pancreatic carcinogenesis and metastatic spread

Abstract Background: Excessive desmoplasia is a typical feature of pancreatic ductal adenocarcinoma (PDAC) and is highly associated with an aggressive tumor phenotype. The main cell population contributing to the stromal response consists of pancreatic stellate cells (PSCs). Periostin, an extracellular matrix protein (ECM), produced by activated PSCs has been shown to have anti-apoptotic and growth-stimulatory effects on pancreatic tumor cells as well as the ability to create a metastatic niche in the secondary target organ. The main signaling route by which periostin mediates its effects is the integrin signaling pathway. Through binding to different integrin subunits the focal adhesion kinase (FAK) gets phosphorylated and downstream signaling pathways such as RAS/ERK/MEK become additionally activated. Aim: Analyzing the function of periostin in early pancreatic carcinogenesis as well as metastatic spread. Methods: A conditional tumor mouse model, expressing oncogenic KrasG12D under the control of a pancreas specific Ptf1a promoter was crossbred with Postn global knockout mice (p48Cre/+;LSL-KrasG12D/+;Postn-/-) and early tumor development was analyzed at two, three and six months of age. In a second approach, a tumor-promoting inflammatory stromal reaction was induced by cerulein injections in p48Cre/+;LSL-KrasG12D/+ mice whereby one group of mice was additionally treated with a daily dose (30mg/kg) of FAK inhibitor. All mice were sacrificed after 7 days and HE staining was performed. Thirdly, to study metastasis formation, murine pancreatic tumor cells were injected into the tail vein of wild type, Postn+/- and Postn-/- mice. After 6 weeks target organs were collected for subsequent analyses. Results: In the early phases, p48Cre/+;LSL-KrasG12D/+;Postn-/- mice displayed less PanIN lesions, fewer atypical ductal structures and reduced proliferating cells. The inhibition of FAK-signaling blocked pancreatic tumorigenesis and absence of periostin abrogated metastatic spread. Conclusion: Periostin produced by the pancreatic stellate cell is necessary both for early carcinogenesis and metastatic spread. The effects of periostin can be antagonized by blocking its downstream pathway using FAK inhibitors. Citation Format: Simone Hausmann, Ivonne Regel, Anna Federlein, Pawel K. Mazur, Katja Steiger, Christoph W. Michalski, Mert Erkan, Jörg Kleeff. The role of periostin in pancreatic carcinogenesis and metastatic spread. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B08.

Role of pancreatic stellate cells and periostin in pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and one of the five most lethal malignancies characterized by prominent desmoplastic reaction. Accumulating evidences indicate that tumor desmoplasia plays a pivotal role in PDAC progression, and it has been largely ignored until recent times. It has now been unequivocally shown that pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Periostin, also known as osteoblast-specific factor 2, is a secretory protein and originally identified as an osteoblast-specific factor that expressed in periosteum. Periostin is exclusively produced by activated PSCs, and periostin overexpression presents in various malignant tumors and closely relates with disease progression. In addition, periostin has been suggested to stimulate pancreatic cancer cells proliferation and enhance their resistance to serum starvation and hypoxia. Therefore, the interplay between cancer cells and stromal cells plays a vital role in PDAC development. However, the function of periostin in pancreatic cancer development is controversial. This review summarizes existing knowledge about the role of PSCs in cancer stroma production, the interaction between PSCs and pancreatic cancer cells, tumor angiogenesis, and hypoxic microenvironment, with particular focus on the expression and function as well as signaling pathways of periostin in PDAC cells and PSCs.

MP49-18 IDENTIFICATION OF EXTRACELLULAR VESICLE PERIOSTIN AS A URINARY BIOMARKER OF MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2015MP49-18 IDENTIFICATION OF EXTRACELLULAR VESICLE PERIOSTIN AS A URINARY BIOMARKER OF MUSCLE INVASIVE BLADDER CANCER Christopher Silvers, Miyamoto Hiroshi, Chia-Hao Wu, Edward Messing, and Yi-Fen Lee Christopher SilversChristopher Silvers More articles by this author , Miyamoto HiroshiMiyamoto Hiroshi More articles by this author , Chia-Hao WuChia-Hao Wu More articles by this author , Edward MessingEdward Messing More articles by this author , and Yi-Fen LeeYi-Fen Lee More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2813AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Periostin is an extracellular matrix protein with roles in cell adhesion and motility and is overexpressed in several cancer types. Multiple microarray dataset analyses of patient tissues have shown periostin mRNA to be overexpressed in muscle-invasive bladder cancer (MIBC), but further investigation has been limited. Extracellular vesicles (EV) are 30-2000 nm membrane-bound structures released by a variety of cell types and bearing a select cargo of proteins and nucleic acids. Our objectives were to investigate functions of periostin in MIBC, the contribution of EV-borne periostin, and the potential of EV periostin as a urinary marker METHODS Multiple bladder cancer cell lines were screened by quantitative real-time PCR (qPCR) for periostin expression. Two highly expressing lines (TCC-SUP and J82) were selected for periostin suppression by RNA interference (shPOSTN). Single clone knockdowns were assessed for changes in morphology, motility, invasiveness, and tumorigenicity in nude mice. EV were isolated and assayed for their ability to affect recipient cells' behaviors. Bladder cancer tissue microarray was performed and periostin expression levels in patients' tumors were correlated to to clinical outcomes. EV were isolated from the urine of MIBC patients and healthy controls, and periostin levels were assayed by Western blot. RESULTS J82 and TCC-SUP cells migrate and invade rapidly and have an extended morphology with long invadopodia. Periostin knockdown significantly slowed migration and invasion and produced a more circular morphology with fewer invadopodia. EV derived from shPOSTN cells had reduced ability to promote migration in recipient cells. Periostin expression in patient MIBC epithelial cells was negatively correlated with progression-free survival (P<0.021) and disease-specific survival (P<0.002). Ten MIBC (pT2-pT4) patient urine EV samples had markedly higher levels of periostin than stage pT1 disease samples (P<0.033), post-TURBT non-MIBC patients (P<0.004), or healthy volunteers (P<0.00003). CONCLUSIONS Periostin plays a heretofore unrecognized role in MIBC. Its expression in bladder cancer epithelial cells is related to the acquisition of an invasive phenotype and may be a promising therapeutic target, and the ability of EV containing high levels of periostin to influence recipient cells invites further study. The easy detectability of periostin in urine EV suggests its suitability as a biomarker of MIBC progression and a possible alternative to expensive cystoscopic surveillance © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e609-e610 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Silvers More articles by this author Miyamoto Hiroshi More articles by this author Chia-Hao Wu More articles by this author Edward Messing More articles by this author Yi-Fen Lee More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...