Periostin Overexpression Research Articles

POSTN promotes the progression of NSCLC via regulating TNFAIP6 expression

Aberrant upregulation of Periostin (POSTN) expression has been implicated in various disease-related pathological cascades, notably inflammatory responses, fibrotic processes and tumor progression, including non-small cell lung cancer (NSCLC). The present study aimed to elucidate the functional role and underlying mechanisms of POSTN in NSCLC. Immunohistochemical and Western blot analysis consistently revealed elevated POSTN levels in NSCLC tissues and cell lines. POSTN expression negatively correlated with patient prognosis. Functional experiments utilizing POSTN-targeting siRNAs demonstrated a significant suppression of NSCLC cell proliferation, epithelial-to-mesenchymal transition (EMT), migration and invasion, whereas POSTN overexpression via plasmid transfection enhanced these oncogenic properties. Mechanistically, RNA sequencing analysis and subsequent validation studies revealed that POSTN positively modulates the transcriptional expression of tumor necrosis factor alpha-induced protein 6 (TNFAIP6) in NSCLC. Notably, a positive correlation was observed between POSTN and TNFAIP6 expression levels, and their overexpression positively correlated with NSCLC progression. Furthermore, TNFAIP6 overexpression rescued the inhibitory effects of POSTN knockdown on NSCLC malignant phenotypes. Collectively, our findings indicate that POSTN promotes NSCLC malignancy through TNFAIP6 upregulation, positioning POSTN as a promising biomarker and potential therapeutic target for NSCLC prognosis and treatment strategies in clinical settings.

Periostin's role in uterine leiomyoma development: a mini-review on the potential periostin poses as a pharmacological intervention for uterine leiomyoma.

Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-β, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-β-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.

Periostin/Bone Morphogenetic Protein 1 axis axis regulates proliferation and osteogenic differentiation of sutured mesenchymal stem cells and affects coronal suture closure in the TWIST1+/− mouse model of craniosynostosis

Background and objectiveThe pathogenesis of coronal suture craniosynostosis is often attributed to the dysregulated cellular dynamics, particularly the excessive proliferation and abnormal osteogenic differentiation of suture cells. Despite its clinical significance, the molecular mechanims of this condition remain inadequately understood. This study is dedicated to exploring the influence of the Periostin/Bone Morphogenetic Protein 1 (BMP1) axis on the growth and osteogenic maturation of Suture Mesenchymal Stem Cells (SMSCs), which are pivotal in suture homeostasis. MethodsNeonatal TWIST Basic Helix-Loop-Helix Transcription Factor 1 heterozygous (TWIST1+/−) mice, aged one day, were subjected to adenoviral vector-mediated Periostin upregulation. To modulate Periostin/BMP1 levels in SMSCs, we employed siRNA and pcDNA 3.1 vectors. Histological and molecular characterizations, including hematoxylin and eosin staining, Western blot, and immunohistochemistry were employed to study suture closure phenotypes and protein expression patterns. Cellular assays, encompassing colony formation, 5-ethynyl-2'deoxyuridine, and wound healing tests were conducted to analyze SMSC proliferation and migration. Osteogenic differentiation was quantified using Alkaline Phosphatase (ALP) and Alizarin Red S (ARS) staining, while protein markers of proliferation and differentiation were evaluated by Western blotting. The direct interaction between Periostin and BMP1 was validated through co-immunoprecipitation assays.ResultsIn the TWIST1+/− model, an upregulation of Periostin coupled with a downregulation of BMP1 was observed. Augmenting Periostin expression mitigated craniosynostosis. In vitro, overexpression of Periostin or BMP1 knockdown suppressed SMSC proliferation, migration, and osteogenic differentiation. Periostin knockdown manifested an inverse biological impact. Notably, the suppressive influence of Periostin overexpression on SMSCs was effectively counteracted by upregulating BMP1. There was a direct interaction between Periostin and BMP1.ConclusionThese findings underscore the significance of the Periostin/BMP1 axis in regulating craniosynostosis and SMSC functions, providing new insights into the molecular mechanisms of craniosynostosis and potential targets for therapeutic intervention.

Endothelial periostin regulates vascular remodeling by promoting endothelial dysfunction in pulmonary arterial hypertension

ABSTRACT Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with extracellular matrix (ECM) deposition, vascular cell hyperproliferation, and neointima formation in the small pulmonary artery. Endothelial dysfunction is considered a key feature in the initiation of vascular remodeling. Although vasodilators have been used for the treatment of PAH, it remains a life-threatening disease. Therefore, it is necessary to identify novel therapeutic targets for PAH treatment. Periostin (POSTN) is a secretory ECM protein involved in physiological and pathological processes, such as tissue remodeling, cell adhesion, migration, and proliferation. Although POSTN has been proposed as a potential target for PAH treatment, its role in endothelial cells has not been fully elucidated. Here, we demonstrated that POSTN upregulation correlates with PAH by analyzing a public microarray conducted on the lung tissues of patients with PAH and biological experimental results from in vivo and in vitro models. Moreover, POSTN overexpression leads to ECM deposition and endothelial abnormalities such as migration. We found that PAH-associated endothelial dysfunction is mediated at least in part by the interaction between POSTN and integrin-linked protein kinase (ILK), followed by activation of nuclear factor-κB signaling. Silencing POSTN or ILK decreases PAH-related stimuli-induced ECM accumulation and attenuates endothelial abnormalities. In conclusion, our study suggests that POSTN serves as a critical regulator of PAH by regulating vascular remodeling, and targeting its role as a potential therapeutic strategy for PAH.

Periostin Protects Against Alcohol-related Liver Disease by Activating Autophagy by Interacting With Protein Disulfide Isomerase

The matricellular protein periostin plays a critical role in liver inflammation, fibrosis, and even carcinoma. Here, the biological function of periostin in alcohol-related liver disease (ALD) was investigated. We used wild-type (WT), Postn-null (Postn-/-) mice and Postn-/- mice with periostin recovery to investigate the biological function of periostin in ALD. Proximity-dependent biotin identification analysis identified the protein that interacted with periostin, and coimmunoprecipitation analysis validated the interaction between protein disulfide isomerase (PDI) and periostin. Pharmacological intervention and genetic knockdown of PDI were used to investigate the functional correlation between periostin and PDI in ALD development. Periostin was markedly upregulated in the livers of mice that were fed ethanol. Interestingly, periostin deficiency severely aggravated ALD in mice, whereas the recovery of periostin in the livers of Postn-/- mice significantly ameliorated ALD. Mechanistic studies showed that the upregulation of periostin alleviated ALD by activating autophagy through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which was verified in murine models treated with the mTOR inhibitor rapamycin and the autophagy inhibitor MHY1485. Furthermore, a protein interaction map of periostin was generated by proximity-dependent biotin identification analysis. Interaction profile analysis identified PDI as a key protein that interacted with periostin. Intriguingly, periostin-mediated enhancement of autophagy by inhibiting the mTORC1 pathway in ALD depended on its interaction with PDI. Moreover, alcohol-induced periostin overexpression was regulated by transcription factor EB. Collectively, these findings clarify a novel biological function and mechanism of periostin in ALD and the periostin-PDI-mTORC1 axis is a critical determinant of ALD.

The Effects of Periostin Expression on Fibroid-Like Transition of Myometrial Cells.

Fibroids, benign tumors of the myometrium, are the most common tumors in women and are associated with spontaneous abortion, preterm birth, placenta abruption, and infertility, among others. The incidence of fibroids in reproductive aged women is 20-89%. Fibroids are characterized by high production of extracellular matrix (ECM), particularly collagens, which play a role in their growth. However, their pathogenesis is poorly understood. Recently, we and others have found periostin (POSTN), a regulatory ECM protein, to be overexpressed in the majority of fibroids analyzed. Periostin is an ECM protein that is a critical regulator and well-established biomarker for fibrosis in tissues such as the lung, skin, and kidney. Our hypothesis was that periostin plays a role in the fibrotic transition of myometrial cells to fibroid cells. To test this, we evaluated the effects of POSTN overexpression in myometrial cells. Telomerase-immortalized myometrial cells were transduced with control or POSTN-overexpression lentivirus particles, generating one control (dCas9-Mock) and two overexpression (dCas9-POSTN-01, dCas9-POSTN-02) cell lines. Overexpression of POSTN in immortalized myometrial cells resulted in a change in phenotype consistent with fibroid cells. They upregulated expression of key fibroid genes and had increased proliferation, adhesion, and migration in vitro. Here, we show a potential role for periostin in the transition of myometrial cells to fibroid cells, giving rationale for future investigation into the role of periostin in fibroid pathogenesis and its potential as a therapeutic target.

Periostin overexpression in scleroderma cardiac tissue and its utility as a marker for disease complications

ObjectiveTo evaluate the levels of periostin in patients with systemic sclerosis (SSc) and their association with features of systemic sclerosis.MethodsThe levels of periostin were assessed in the serum of 106 SSc patients and 22 healthy controls and by immunofluorescence staining in cardiac tissue from 4 SSc patients and 4 controls. Serum periostin was measured via enzyme-linked immunosorbent assay. The results were analyzed using Mann-Whitney test or Kruskal-Wallis test followed by Dunn’s multiple comparisons tests and Spearman’s test for correlations. Cardiac tissue from SSc patients and controls was stained for periostin and co-stained for periostin and collagen type I using immunofluorescence.ResultsPeriostin levels were higher in patients with SSc compared to controls and directly correlated to modified Rodnan skin score and echocardiography parameters of left ventricular measurements. Immunofluorescence staining in SSc cardiac tissue showed patchy periostin expression in all SSc patients, but not in controls. Furthermore, there was extensive periostin expression even in areas without collagen deposition, while all established fibrotic areas showed colocalization of collagen and periostin. There was no association between periostin levels and interstitial lung disease, pulmonary hypertension or other vascular complications.ConclusionPeriostin is elevated in SSc cardiac tissue in vivo and circulating levels of periostin are increased in SSc, correlating with the extent of disease duration, degree of skin fibrosis, and left ventricular structural assessments. Periostin may be a potential biomarker that can provide further pathogenic insight into cardiac fibrosis in SSc.

Periostin contributes to the adventitial remodeling of atherosclerosis by activating adventitial fibroblasts

Background and aimsAdventitial remodeling is an important pathological process of atherosclerosis, but cues implicated in adventitial remodeling are far from fully understood. Periostin (POSTN), a matricellular protein, has been demonstrated to have multiple roles in cardiovascular diseases. The aim of the study was to explore the function of POSTN in adventitial remodeling during atherosclerosis. MethodsAn atherosclerosis model was constructed based on ApoE-/- mice fed a high-fat and high-cholesterol diet. The expression of POSTN in the adventitia of mouse atherosclerotic vascular specimens was detected by immunohistochemical staining. The roles of POSTN in regulating adventitial fibroblast activation were assessed by cell contractility and activation marker α-smooth muscle actin (α-SMA) expression evaluation in adventitial fibroblasts overexpressing POSTN. In addition, we performed quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting to examine the expression of the proinflammatory chemokines transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein 1 (MCP1), as well as some extracellular matrix (ECM)-related proteins, in POSTN-overexpressing adventitial fibroblasts. Finally, the integrin-related signaling pathway was detected upon POSTN overexpression in adventitial fibroblasts. ResultsPOSTN was highly expressed in the adventitia of atherosclerotic aortae in the mouse atherosclerosis model and promoted the activation and contraction of adventitial fibroblasts. Meanwhile, POSTN also induced adventitial fibroblasts to express TGF-β1, monocyte chemotactic protein-1 (MCP1), and ECM-related proteins and activated the phosphorylation of focal adhesion kinase (FAK) and Src. ConclusionsOur results revealed that POSTN is elevated in adventitia during atherosclerosis and contributes to the adventitial remodeling of atherosclerosis by activating adventitial fibroblasts.

Prognostic impact of stromal periostin expression in upper urinary tract urothelial carcinoma

BackgroundPeriostin is an extracellular matrix protein that has been known to be implicated in fibrillogenesis and cell migration, including cancer metastasis. Periostin overexpression in cancer cells and/or intervening stroma is usually related to tumor progression and poor patient outcomes in various human cancers; however, its role in urothelial carcinoma, especially upper urinary tract urothelial carcinomas (UTUCs), remains inconclusive.MethodsSamples from 126 consecutive cases of invasive UTUC (69 renal pelvic cancers and 57 ureteral cancers) were histologically reviewed and analyzed for periostin expression using immunohistochemistry. The intensities of immunoreactivity and the fraction of positive cancer cells and stroma (i.e., epithelial and stromal expression, respectively) were classified into four categories each (intensity, 0–3; fraction, 0–25% = 1; 26–50% = 2; 51–75% = 3; and > 75% = 4). The overall score was determined by multiplying both scores, and overall scores ≥ 6 were considered to indicate high periostin expression.ResultsAmong 126 UTUCs, 55 (44%; 27 renal pelvic and 28 ureteral cancers) showed high stromal periostin expression. None of the cases were considered to have high epithelial periostin expression. High stromal periostin expression was associated with non-papillary gross findings, higher pathological T category, lymphovascular invasion, concomitant carcinoma in situ, subtype histology, lymph node metastasis, positive surgical margins, high tumor budding, and high tumor-associated immune cell status. Multivariate analysis revealed that high stromal periostin expression was an independent predictor of overall survival (p = 0.00072, hazard ratio = 3.62), and lymphovascular invasion and high stromal periostin expression were independent predictors of cancer-specific survival (p = 0.032 and 0.020, hazard ratio = 2.61 and 3.07, respectively).ConclusionsStromal periostin expression was often observed in invasive UTUCs with adverse clinicopathological factors and may be a useful predictor of patient outcomes.

Periostin Short Fragment with Exon 17 via Aberrant Alternative Splicing Is Required for Breast Cancer Growth and Metastasis.

Background: Periostin (POSTN) is a 93 kDa matrix protein that helps to regulate collagen gene expression in the extracellular matrix. POSTN overexpression is a prognostic factor in malignant cancers; however, some researchers have observed it in the stroma, whereas others have reported it on tumors. Objective: This study aimed to investigate the function of POSTN on tumors. Methods and Results: We found that POSTN in cancer cells can be detected by using an antibody against the POSTN C-terminal region exon 17 (Ex17 antibody), but not with an antibody against the POSTN N-terminal region exon 12 (Ex12 antibody) in patients with breast cancer. In a fraction secreted from fibroblasts, LC–MS/MS analysis revealed a short fragment of POSTN of approximately 40 kDa with exon 17. In addition, molecular interaction analysis showed that POSTN with exon 17, but not POSTN without exon 17, bound specifically to wnt3a, and the Ex17 antibody inhibited the binding. Conclusion: A short fragment of POSTN with exon 17, which originates in the fibroblasts, is transported to cancer cells, whereas POSTN fragments without exon 17 are retained in the stroma. The Ex17 antibody inhibits the binding between POSTN exon 17 and wnt3a.

Development of an engineered peptide antagonist against periostin to overcome doxorubicin resistance in breast cancer

BackgroundChemoresistance is one of the main problems in treatment of cancer. Periostin (PN) is a stromal protein which is mostly secreted from cancer associated fibroblasts in the tumor microenvironment and can promote cancer progression including cell survival, metastasis, and chemoresistance. The main objective of this study was to develop an anti-PN peptide from the bacteriophage library to overcome PN effects in breast cancer (BCA) cells.MethodsA twelve amino acids bacteriophage display library was used for biopanning against the PN active site. A selected clone was sequenced and analyzed for peptide primary structure. A peptide was synthesized and tested for the binding affinity to PN. PN effects including a proliferation, migration and a drug sensitivity test were performed using PN overexpression BCA cells or PN treatment and inhibited by an anti-PN peptide. An intracellular signaling mechanism of inhibition was studied by western blot analysis. Lastly, PN expressions in BCA patients were analyzed along with clinical data.ResultsThe results showed that a candidate anti-PN peptide was synthesized and showed affinity binding to PN. PN could increase proliferation and migration of BCA cells and these effects could be inhibited by an anti-PN peptide. There was significant resistance to doxorubicin in PN-overexpressed BCA cells and this effect could be reversed by an anti-PN peptide in associations with phosphorylation of AKT and expression of survivin. In BCA patients, serum PN showed a correlation with tissue PN expression but there was no significant correlation with clinical data.ConclusionsThis finding supports that anti-PN peptide is expected to be used in the development of peptide therapy to reduce PN-induced chemoresistance in BCA.

Periostin regulates osteogenesis of mesenchymal stem cells from ovariectomized rats through actions on the ILK/Akt/GSK-3β Axis.

Osteoporosis is a condition of the skeleton that mainly results from estrogen deficiency. Periostin is a matricellular component in bone that is involved in osteoblast differentiation. However, how Periostin promotes osteogenesis remains largely unknown. Here, we isolated bone marrow skeletal stem cells (BMSCs) derived from an ovariectomy (OVX)-induced osteoporosis rat model and the effects of periostin on BMSCs derived from OVX rats (OVX-BMSCs) were assessed. Overexpression of periostin enhanced alkaline phosphatase (ALP) and alizarin red staining in OVX-BMSCs as well as the osteogenic genes OCN, BSP and Runx2. ILK is a downstream effector of signals from the extracellular matrix and participates in bone homeostasis. Overexpression of periostin also increased expression of protein levels for ILK, as well as the downstream targets pAkt and pGSK3β. Suppression of ILK or Akt partially suppressed the enhancement of osteogenic ability induced by periostin overexpression in OVX-BMSCs. Thus, periostin may promote the osteogenic ability of OVX-BMSCs through actions on the ILK/Akt/GSK3β axis.

POSTN promotes proliferation and epithelial-mesenchymal transition in renal cell carcinoma through ILK/AKT/mTOR pathway.

Periostin (POSTN) is an extracellular matrix (ECM) protein, involved in various diseases. This research focused on the detailed mechanisms study of periostin (POSTN) overexpression in renal cell carcinoma (RCC) invasion and migration. Western blot and RT-PCR were performed to explore POSTN expression in various RCC cells. Cells were transfected with siRNAs or lentivirus to regulate the expression of POSTN. The effects of POSTN on cell viability, apoptosis, migration, invasion and epithelial-to-mesenchymal transition (EMT) of RCC cells were determined by CCK-8, flow cytometry, migration and invasion assay and Western blot analysis. POSTN expression was significantly enhanced in RCC cells compared with renal tubular epithelial cells. In vitro experiments showed that POSTN knockdown could dramatically inhibit RCC cell proliferation, migration and invasion, while overexpression of POSTN could promote these biological behaviors. We further demonstrated that POSTN knockdown suppressed epithelial-mesenchymal transition (EMT), which was mediated via upregulation of E-cadherin and downregulation of N-cadherin and vimentin, through IKL/AKT/mTOR pathway. In contrast, overexpression of POSTN could promote EMT in RCC cells via the activation of IKL /AKT/mTOR pathway. Next, we demonstrated that higher POSTN expression promoted angiogenesis in vivo in an RCC xenograft tumor via activating IKL /AKT/mTOR pathway. Our study showed that POSTN could promote EMT through ILK/AKT/mTOR pathway and might be an alternative therapeutic strategy for RCC treatment.

Periostin Mediates Oestrogen-Induced Osteogenic Differentiation of Bone Marrow Stromal Cells in Ovariectomised Rats.

Osteoporosis is a metabolic disease that results in the progressive loss of bone mass, which, in postmenopausal women, is related to oestrogen deficiency. Periostin (POSTN) plays a key role in the early stages of bone formation. However, whether POSTN participates in oestradiol regulation of osteogenic differentiation of bone marrow stromal cells (BMSCs) from ovariectomised (OVX) rats remains unclear. In vivo, using microcomputed tomography (micro-CT), immunohistochemistry, and dynamic analysis of femurs, we found that 17β-E2 promotes bone formation and POSTN expression at the endosteal surface. In vitro, 17β-E2 upregulated POSTN expression in OVX-BMSCs. POSTN overexpression activated the Wnt/β-catenin signalling pathway and enhanced osteogenic differentiation of OVX-BMSCs. Furthermore, knockdown of Postn blocks the involvement of 17β-E2 in the osteogenic differentiation of OVX-BMSCs. Collectively, our study indicated the role of POSTN in the osteogenesis and stemness of OVX-BMSCs and proves that 17β-E2 reduces osteoporosis and promotes osteogenesis through the POSTN-Wnt/β-catenin pathway. POSTN could, therefore, be a novel target gene for anti-osteoporosis therapies.

Periostin Promotes Cell Proliferation and Macrophage Polarization to Drive Repair after AKI.

The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown. We used mice with conditional tubule-specific overexpression of periostin or knockout mice lacking periostin expression in the renal ischemia-reperfusion injury model, and primary cultures of isolated tubular cells in a hypoxia-reoxygenation model. Tubular epithelial cells showed strong production of periostin during the repair phase of ischemia reperfusion. Periostin overexpression protected mice from renal injury compared with controls, whereas knockout mice showed increased tubular injury and deteriorated renal function. Periostin interacted with its receptor, integrin-β1, to inhibit tubular cell cycle arrest and apoptosis in in vivo and in vitro models. After ischemia-reperfusion injury, periostin-overexpressing mice exhibited diminished expression of proinflammatory molecules and had more F4/80+ macrophages compared with knockout mice. Macrophages from periostin-overexpressing mice showed increased proliferation and expression of proregenerative factors after ischemia-reperfusion injury, whereas knockout mice exhibited the opposite. Coculturing a macrophage cell line with hypoxia-treated primary tubules overexpressing periostin, or treating such macrophages with recombinant periostin, directly induced macrophage proliferation and expression of proregenerative molecules. In contrast to the detrimental role of periostin in CKD, we discovered a protective role of periostin in AKI. Our findings suggest periostin may be a novel and important mediator of mechanisms controlling renal repair after AKI.

Prognostic value of periostin in multiple solid cancers: A systematic review with meta-analysis.

Previous studies have shown that the expression of periostin (POSTN) is significantly correlated with prognosis in multiple solid cancers. However, the function of POSTN in tumorigenesis and its relationship with clinical outcomes have not been systematically summarized and analyzed. Thus, a meta-analysis was performed to evaluate the prognostic pertinence of POSTN in solid cancer. We conducted a systematic search in the PubMed, EMBASE, Web of Science, and Cochrane library databases, and a total of 10 studies were used to assess the association of POSTN expression and patients' overall survival (OS) and disease-free survival (DFS). The hazard ratio (HR) or odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate the association between POSTN and relevant clinical parameters of solid cancer patients. The pooled results indicated that POSTN overexpression was associated with poor OS (HR = 2.35, 95% CI = 1.88-2.93, p < .00001) and DFS (HR = 2.70, 95% CI = 2.00-3.65, p < .00001) in a cohort of 993 patients with cancer. Subsequent analyses showed that the positive expression ratio of POSTN was evidently higher in cancer tissues than in normal tissues (OR = 7.44, 95% CI = 3.66-13.95, p < .00001). In addition, subgroup analysis showed that POSTN was related to microvascular invasion (OR = 5.09, 95% CI = 3.07-8.44, p < .00001), tumor differentiation (OR = 2.03, 95% CI = 1.41-2.91, p = .0001), and lymph node metastasis (OR = 3.05, 95% CI = 2.01-4.64, p < .00001). These data showed that POSTN could be a credible prognostic biomarker and a potential therapeutic target in human solid cancer.

Knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal renin-angiotensin system activation, fibrosis, and inflammation in rats.

To simulate clinical features in human chronic kidney disease (CKD), SD rats were subjected to 5/6 nephrectomy in this study. We found that periostin gene was upregulated in the remnant kidneys using Agilent gene microarrays, and further explored its role via in vivo and in vitro experiments. Intrarenal renin-angiotensin system (RAS) was activated in 5/6 nephrectomized rats and partly deactivated by injection of adenoviruses encoding short hairpin RNA against periostin (sh-periostin). Renal fibrosis in nephrectomized rats and profibrotic transforming growth factor-β-induced epithelial-mesenchymal transition (EMT) and ERK1/2 activation in NRK-52E cells were suppressed by sh-periostin. Moreover, knockdown of periostin decreased the generation of Interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α) and accelerated p62 degradation in the remnant kidneys. Both HK-2 cells treated with recombinant periostin and NRK-52E cells infected with adenoviruses expressing periostin produced more IL6 and TNF-α than control cells and displayed impaired autophagy as evidenced by inhibition of LC3II to LC3I conversion, Beclin 1 expression, and p62 degradation. By treating cells with rapamycin, an inhibitor of mamalian target of rapamycin known to activate autophagy, we noted that periostin-induced inflammation was inhibited. Additionally, HK-2 cells transfected with periostin overexpression plasmid generated more CCL2 and CXCL10, two important chemotactic factors, than untransfected cells. Conditioned medium from HK-2 cells overexpressing periostin augmented chemotaxis of THP-1 macrophages. Collectively, our work demonstrates that knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal RAS activation, fibrosis, and inflammation in rats. These findings advance our understanding of periostin's role in CKD induced by nephron loss.

LncRNA H19/miR-let-7 axis participates in the regulation of ox-LDL-induced endothelial cell injury via targeting periostin

Oxidized-low density lipoprotein (ox-LDL)-induced endothelial cell dysfunction is a crucial event in the pathogenesis of atherosclerosis (AS). Long noncoding RNAs (lncRNAs) have been shown to play important roles in this process. The purpose of this study was to investigate the biological effects of lncRNA H19 on the ox-LDL-induced endothelial cell injury and to explore the underlying molecular mechanisms. In the present study, the expression of H19 in the serum of patients with AS and in the ox-LDL-treated human umbilical vein endothelial cells (HUVECs) was significantly up-regulated. H19 knockdown by transfection with H19 siRNAs in ox-LDL-treated HUVECs remarkably promoted cell viability, suppressed the secretion of interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α, decreased the expression of vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1) and E-selectin, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) levels, and reduced cell apoptosis. Moreover, H19 knockdown significantly down-regulated the ox-LDL-induced expression of periostin, but did not affect the expression of let-7a, which directly targets the 3′-UTR of periostin mRNA. In addition, periostin overexpression partly reversed the biological effects of H19 knockdown in ox-LDL-treated HUVECs, which were almost recapitulated by let-7 overexpression. In conclusion, these data suggest that H19 knockdown suppressed ox-LDL-induced inflammation, apoptosis and oxidative stress in HUVECs, which may be related to the down-regulation of periostin by interfering with let-7 bioavailability.

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease

In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds αVβ3-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. By contrast, periostin does not stimulate the proliferation of normal human kidney cells. This difference in the response to periostin is due to elevated expression of αVβ3-integrins by cystic cells. To determine whether periostin accelerates cyst growth and fibrosis, we generated mice with conditional overexpression of periostin in the collecting ducts (CDs). Ectopic CD expression of periostin was not sufficient to induce cyst formation or fibrosis in wild-type mice. However, periostin overexpression in pcy/pcy ( pcy) kidneys significantly increased mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis; and accelerated the decline in renal function. Moreover, CD-specific overexpression of periostin caused a decrease in the survival of pcy mice. These pathological changes were accompanied by increased renal expression of vimentin, α-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD.

Periostin overexpression is associated with worse prognosis in nasopharyngeal carcinoma from endemic area: a cohort study.

PurposeNasopharyngeal carcinoma (NPC) is a heterogeneous disease. We searched for genes that function in cell adhesion in GSE12452, a published transcriptomic database. We found that POSTN, which encodes periostin (POSTN), was significantly upregulated in NPC tumorigenesis. Herein, we sought to analyze the expression of POSTN and its prognostic significances in patients with NPC.Materials and methodsIn this single-institution retrospective study, we determined and analyzed POSTN expression by immunohistochemistry and H-score method, respectively, in 124 patients with NPC. The results indicated that POSTN expression was correlated with the clinicopathologic features, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS) of NPC. We performed univariate and multivariate analyses to determinate the statistical significance.ResultsHigh POSTN expression was significantly associated with lymph node metastasis (p=0.004) and advanced American Joint Committee on Cancer (AJCC) stage (p=0.006). In univariate analysis, high POSTN expression served as a significant prognostic factor for worse DSS (p=0.0002), DMFS (p=0.0138), and LRFS (p=0.0028). In multivariate Cox regression analyses, which was adjusted for AJCC stages, POSTN expression was independently associated with cancer-related death (HR: 2.311; 95% CI: 1.327–4.027; p=0.003) and local tumor recurrence (HR: 3.187; 95% CI: 1.108–4.408; p=0.024).ConclusionHigh POSTN expression is associated with tumor aggressiveness and worse clinical outcomes in NPC, indicating that it may be a potential prognostic biomarker and a therapeutic target.