SPP1

Gene Summary

Gene:SPP1; secreted phosphoprotein 1
Aliases: OPN, BNSP, BSPI, ETA-1
Location:4q22.1
Summary:The protein encoded by this gene is involved in the attachment of osteoclasts to the mineralized bone matrix. The encoded protein is secreted and binds hydroxyapatite with high affinity. The osteoclast vitronectin receptor is found in the cell membrane and may be involved in the binding to this protein. This protein is also a cytokine that upregulates expression of interferon-gamma and interleukin-12. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:osteopontin
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SPP1 (cancer-related)

Kamal A, Darwish RK, Saad S, et al.
Association of Osteopontin Gene Polymorphisms with Colorectal Cancer.
Cancer Invest. 2017; 35(2):71-77 [PubMed] Related Publications
We investigated the association of the Osteopontin (OPN) (rs9138 and rs1126616) polymorphisms with colorectal cancer (CRC). One hundred CRC patients and 112 healthy individuals were subjected to OPN (rs9138 and rs1126616) genotyping and measurement of OPN protein plasma level. The C allele of OPN rs1126616 and the CC haplotype were significantly higher in CRC patient (p = 0.036, 0.003, respectively). In females, the C allele of OPN rs9318 (A/C) polymorphism was significantly associated with increased CRC risk (p = 0.036). The plasma OPN level >104.35 ng/mL was significantly associated with CRC. Our findings suggest a significant role played by OPN (rs9138 and rs1126616) in colorectal carcinogenesis.

Zhuo C, Li X, Zhuang H, et al.
Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis.
Cell Physiol Biochem. 2016; 40(6):1316-1324 [PubMed] Related Publications
BACKGROUND/AIMS: Gastric cancer (GC) is an important health problem. Classification based on molecular subtypes may help to determine the prognosis of patients with GC. Tumor invasion and metastasis are important factors affecting the prognosis of cancer. We aimed to identify genes related to tumor invasion and metastasis, which may serve as indicators of good GC prognosis.
METHODS: Tumor tissues and adjacent normal tissues were collected from 105 patients with primary GC who were treated by undergoing radical surgery. Samples were used for tissue microarray analysis. Identified genes with altered expression were further analyzed using the Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The expression levels of THBS2, COL1A2 and SPP1 were analyzed by RT-PCR, western blot and immunohistochemistry. The overall survival curves of patients with high and low expression of each gene of interest were plotted and compared.
RESULTS: Forty-three genes were identified. THBS2, COL1A2 and SPP1 were selected for further analysis. Altered expression levels of THBS2, COL1A2 and SPP1 in tumor tissues were confirmed. Patients with low THBS2 expression had a better prognosis; the expression of COL1A2 and SPP1 might not affect the prognosis of patients with GC.
CONCLUSION: THBS2, but not COL1A2 and SPP1, may serve as an indicator of GC prognosis.

Boguslawska J, Sokol E, Rybicka B, et al.
microRNAs target SRSF7 splicing factor to modulate the expression of osteopontin splice variants in renal cancer cells.
Gene. 2016; 595(2):142-149 [PubMed] Related Publications
SRSF7 is a SR splicing factor involved in the regulation of splicing and mRNA export of cancer-related genes. The mechanisms regulating the expression of SRSF7 are unknown. This study shows that SRSF7 expression in cancer cells is regulated by microRNAs: short, non-coding RNAs that bind to 3'UTR of target genes and downregulate their expression. We show that microRNAs miR-30a-5p and miR-181a-5p together with SRSF7 form regulatory feedback loop in which the expression of microRNAs is recurrently regulated by its target. Finally, we demonstrate that silencing of SRSF7 affects the expression of osteopontin splice variants and decreases proliferation rate of renal cancer cells.

Hass HG, Vogel U, Scheurlen M, Jobst J
Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(10):5087-5095 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation.
MATERIALS AND METHODS: DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples.
RESULTS: Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis.
CONCLUSION: It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.

Teixeira LN, de Castro Raucci LM, Alonso GC, et al.
Osteopontin expression in co-cultures of human squamous cell carcinoma-derived cells and osteoblastic cells and its effects on the neoplastic cell phenotype and osteoclastic activation.
Tumour Biol. 2016; 37(9):12371-12385 [PubMed] Related Publications
This study evaluated the temporal expression of osteopontin (OPN) in co-cultures of human osteoblastic cells (SAOS-2) and oral squamous cell carcinoma (OSCC)-derived cells (SCC9) and examined the effects of osteoblast-derived OPN on the neoplastic cell phenotype. Additionally, the effects of these co-cultures on subsequent osteoclastic activity were explored. SCC9 cells were plated on Transwell® membranes that were either coated or not coated with Matrigel and were then co-cultured with SAOS-2 cells during the peak of OPN expression. SCC9 cells exposed to OPN-silenced SAOS-2 cultures and SCC9 cells cultured alone served as controls. SCC9 cells were quantitatively evaluated for cell adhesion, proliferation, migration, and invasion into Matrigel. The impact of co-culturing SAOS-2 and SCC9 cells on the resorptive capacity of U-937-derived osteoclastic cells was also investigated. Furthermore, a reciprocal induction of SAOS-2 and SCC9 cells in terms of OPN expression over the co-culture interval was identified. SAOS-2-secreted OPN altered the SCC9 cell phenotype, leading to enhanced cell adhesion and proliferation and higher Matrigel invasion. This invasion was also enhanced, albeit to a lesser degree, by co-culture with OPN-silenced SAOS-2 cells. Cell migration was not affected. Co-culture with SAOS-2 cells-mainly during the period of peak OPN expression-promoted over-expression of IL-6 and IL-8 by SCC9 cells and enhanced the resorptive capacity of osteoclastic cells. Taken together, these results suggest that osteoblast-derived OPN affects the interactions among OSCC-derived epithelial cells, osteoblasts, and osteoclasts, which could contribute to the process of bone destruction during bone invasion by OSCC.

Kostianets O, Shyyan M, Antoniuk SV, et al.
Panel of SEREX-defined antigens for breast cancer autoantibodies profile detection.
Biomarkers. 2017; 22(2):149-156 [PubMed] Related Publications
CONTENT: Identification of panel of SEREX-defined antigens for breast cancer autoantibodies profile detection.
OBJECTIVE: To create panel of antigens that can differentiate breast cancer patients and healthy individuals.
METHODS: SEREX (serological analysis of cDNA expression libraries) method, ELISA (enzyme-linked immunosorbent assay), qPCR (quantitative polymerase chain reaction).
RESULTS: In large-scale screening of 16 SEREX-antigens by sera of breast cancer patients and healthy donors, a combination of six antigens (RAD50, PARD3, SPP1, SAP30BP, NY-BR-62 and NY-CO-58) was identified, which can differentiate breast cancer patients and healthy donors with 70% sensitivity and 91% specificity. Elevated mRNA expression of SPP1 gene was revealed in breast tumors (2-7-fold) that correlated with SPP1 antigen immunoreactivity in autologous patients' sera.
CONCLUSIONS: The new panel of six SEREX-antigens was proposed, which enables creation of serological assay for breast cancer diagnostics and/or prognosis.

Zhang J, Yamada O, Kida S, et al.
Identification of brefelamide as a novel inhibitor of osteopontin that suppresses invasion of A549 lung cancer cells.
Oncol Rep. 2016; 36(4):2357-64 [PubMed] Related Publications
The contribution of aberrant osteopontin (OPN) expression to tumor progression and metastasis has been documented in a wide spectrum of malignancies, and targeted inhibition of OPN has therefore emerged as an attractive strategy for cancer therapy. Transcription of OPN is regulated by various transcription factors, and our recently published study demonstrated that downregulation of OPN is an important event in the TGF‑β cytostatic program. We report here that brefelamide exerts an inhibitory effect on OPN expression and function in A549 human lung carcinoma cells. The promoter, RNA, and protein levels of OPN were decreased in brefelamide‑treated A549 cells, which was accompanied by reduced invasive ability in vitro. OPN inhibition by brefelamide was largely abrogated by disruption of a putative TGF‑β inhibitory element in the OPN promoter. Treatment with brefelamide induced Smad4 expression, and knockdown of Smad4 by RNA interference partially diminished the inhibitory effect of brefelamide on OPN. These results indicate that brefelamide inhibited OPN‑mediated cell invasion through restoration of the OPN repression by TGF‑β/Smad signaling. Together with the reported antiproliferative property, our findings suggest that brefelamide might serve as a potential candidate for the development of a new antitumor and antimetastatic agent.

Hao C, Wang Z, Gu Y, et al.
Prognostic Value of Osteopontin Splice Variant-c Expression in Breast Cancers: A Meta-Analysis.
Biomed Res Int. 2016; 2016:7310694 [PubMed] Free Access to Full Article Related Publications
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.

Abdulrahman N, Jaballah M, Poomakkoth N, et al.
Inhibition of p90 ribosomal S6 kinase attenuates cell migration and proliferation of the human lung adenocarcinoma through phospho-GSK-3β and osteopontin.
Mol Cell Biochem. 2016; 418(1-2):21-9 [PubMed] Related Publications
p90 ribosomal S6 kinase (p90RSK) constitutes a family of serine/threonine kinases that have been shown to be involved in cell proliferation of various malignancies via direct or indirect effects on the cell-cycle machinery. We investigated the role of p90RSK in lung adenocarcinomas and whether the inhibition of p90RSK diminishes cancer progression. Moreover, we investigated the involvement of glycogen synthase kinase-3β (GSK-3β) and osteopontin (OPN) in the p90RSK-induced lung adenocarcinoma progression. p90RSK, OPN, and GSK-3β protein expressions were examined in the A549 human lung adenocarcinoma cell line in the presence and absence of BI-D1870 (BID), a p90RSK inhibitor. Gene expression of anti-apoptotic and pro-apoptotic markers namely Bcl2 and Bax, respectively, were studied by reverse transcription polymerase chain reaction. In addition, the A549 lung adenocarcinoma cell line was characterized for cell proliferation using the MTT assay and cell migration using the scratch migration assay. Our study revealed that total RSK1 protein expression is over expressed in the A549 human lung adenocarcinoma cell line, an effect which is significantly reduced upon pretreatment with BID (69.32 ± 12.41 % of control; P < 0.05). The inhibition of p90RSK also showed a significant suppression of cell proliferation (54.3 ± 6.73 % of control; P < 0.01) and cell migration (187.90 ± 16.10 % of control; P < 0.01). Treatment of the A549 cells with BID regressed the expression of Bcl2 mRNA (56.92 ± 6.07 % of control; P < 0.01). BID also regressed protein expression of OPN (79.57 ± 5.32 % of control; P < 0.05) and phospho-GSK-3β (73.04 ± 8.95 % of control; P < 0.05). The p90RSK has an essential role in promoting tumor growth and proliferation in non-small cell lung cancer (NSCLC). BID may serve as an alternative cancer treatment in NSCLC.

Viloria K, Hill NJ
Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation.
Biomol Concepts. 2016; 7(2):117-32 [PubMed] Related Publications
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.

Shi SM, Su ZB, Zhao JJ, et al.
Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: A meta analysis.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):277-82 [PubMed] Related Publications
AIM: The present meta-nalysis investigates the prognostic value of osteopontin. (OPN) expression in patients with non-small-cell lung cancer. (NSCLC).
MATERIALS AND METHODS: The Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched, without language restrictions, to retrieve studies related to OPN and NSCLC. We compiled carefully selected data and a meta-analysis was conducted using STATA software (Version 12.0, Stata Corporation, and College Station, Texas USA). Hazard ratios (HR) with corresponding 95% confidence interval (95%CI) were calculated.
RESULTS: Ten clinical cohort studies were selected for statistical analysis, representing a total of 1,133 NSCLC patients. The main findings of our meta-analysis are that patients who were OPN-positive had significantly shorter overall survival than OPN-negative patients. (HR = 1.47, 95%CI = 1.15. ~ 1.79,P< 0.001). Ethnicity.stratified analysis revealed a significant correlation between expression levels of OPN and poor prognosis of NSCLC patients among both Caucasians and Asians. (Asians: HR = 1.53, 95%CI = 0.95. ~ 2.11, P < 0.001; Caucasians: HR = 1.56, 95%CI = 1.08. ~ 2.03, P < 0.001; respectively).
CONCLUSIONS: The present meta-analysis is consistent with the hypothesis that increased expression of OPN protein may be significantly associated with poor prognosis in patients with NSCLC.

van der Velden VH, de Launaij D, de Vries JF, et al.
New cellular markers at diagnosis are associated with isolated central nervous system relapse in paediatric B-cell precursor acute lymphoblastic leukaemia.
Br J Haematol. 2016; 172(5):769-81 [PubMed] Related Publications
In childhood acute lymphoblastic leukaemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Using microarray-analysis, we discovered multiple differentially expressed genes between B-cell precursor (BCP) ALL cells in bone marrow (BM) and BCP-ALL cells in cerebrospinal fluid (CSF) at the time of isolated CNS relapse. After confirmation by real-time quantitative polymerase chain reaction, selected genes (including SCD and SPP1) were validated at the protein level by flowcytometric analysis of BCP-ALL cells in CSF. Further flowcytometric validation showed that a subpopulation of BCP-ALL cells (>1%) with a 'CNS protein profile' (SCD positivity and increased SPP1 expression) was present in the BM at diagnosis in patients who later developed an isolated CNS relapse, whereas this subpopulation was <1% or absent in all other patients. These data indicate that the presence of a (small) subpopulation of BCP-ALL cells with a 'CNS protein profile' at diagnosis (particularly SCD-positivity) is associated with isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.

Rabjerg M, Bjerregaard H, Halekoh U, et al.
Molecular characterization of clear cell renal cell carcinoma identifies CSNK2A1, SPP1 and DEFB1 as promising novel prognostic markers.
APMIS. 2016; 124(5):372-83 [PubMed] Related Publications
The prognosis associated with clear cell renal carcinoma (ccRCC) can vary widely and novel molecular prognostic markers are needed to assess prognosis at an earlier stage. Several gene products have been investigated for this purpose, but none of them have been implemented in clinical practice. Here we hypothesized that we, using TaqMan® Array, could identify superior prognostic messenger RNA (mRNA)s in long-term follow-up. Messenger RNA level of 19 candidate genes was investigated in 97 patients with ccRCC. Three genes impacted significantly on prognosis in both univariate and multivariate analysis. In univariate analysis, CSNK2A1 was a strong indicator of a poor overall survival (OS) (HR = 5.01, p < 0.001), disease specific survival (DSS) (HR = 6.21, p = 0.007) and progression free survival (PFS) (HR = 5.93, p = 0.005). High expression of SPP1 was associated to poor PFS (HR = 4.41, p = 0.04). DEFB1 was associated with a better PFS (HR = 0.24, p = 0.006). In multivariate analysis, CSNK2A1 was associated to a worse OS (HR = 3.56, p = 0.008) and PFS (HR = 3.84, p = 0.005), whereas SPP1 was an independent predictor of a worse PFS (HR = 3.46, p = 0.007) and DEFB1 of a better PFS (HR = 0.37, p = 0.027). These results show that with TaqMan®) Array we could identify three superior gene products related to prognosis. Further studies are needed to elucidate the pathways and roles of these genes in renal cacer development.

Mengual L, Lozano JJ, Ingelmo-Torres M, et al.
Using gene expression from urine sediment to diagnose prostate cancer: development of a new multiplex mRNA urine test and validation of current biomarkers.
BMC Cancer. 2016; 16:76 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Additional accurate non-invasive biomarkers are needed in the clinical setting to improve prostate cancer (PCa) diagnosis. Here we have developed a new and improved multiplex mRNA urine test to detect prostate cancer (PCa). Furthermore, we have validated the PCA3 urinary transcript and some panels of urinary transcripts previously reported as useful diagnostic biomarkers for PCa in our cohort.
METHODS: Post-prostatic massage urine samples were prospectively collected from PCa patients and controls. Expression levels of 42 target genes selected from our previous studies and from the literature were studied in 224 post-prostatic massage urine sediments by quantitative PCR. Univariate logistic regression was used to identify individual PCa predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination was measured by ROC curve AUC for both, our model and the previously published biomarkers.
RESULTS: Seven of the 42 genes evaluated (PCA3, ELF3, HIST1H2BG, MYO6, GALNT3, PHF12 and GDF15) were found to be independent predictors for discriminating patients with PCa from controls. We developed a four-gene expression signature (HIST1H2BG, SPP1, ELF3 and PCA3) with a sensitivity of 77% and a specificity of 67% (AUC = 0.763) for discriminating between tumor and control urines. The accuracy of PCA3 and previously reported panels of biomarkers is roughly maintained in our cohort.
CONCLUSIONS: Our four-gene expression signature outperforms PCA3 as well as previously reported panels of biomarkers to predict PCa risk. This study suggests that a urinary biomarker panel could improve PCa detection. However, the accuracy of the panels of urinary transcripts developed to date, including our signature, is not high enough to warrant using them routinely in a clinical setting.

Laohaviroj M, Chamgramol Y, Pairojkul C, et al.
Clinicopathological Significance of Osteopontin in Cholangiocarcinoma Cases.
Asian Pac J Cancer Prev. 2016; 17(1):201-5 [PubMed] Free Access to Full Article Related Publications
Cholangiocarcinoma (CCA) is generally a rare primary liver tumor of the bile duct with extremely poor clinical outcomes due to late diagnosis. Osteopontin (OPN) is the most abundant expressed gene in intrahepatic CCA and its involvement in tumor aggressiveness suggests it could be a useful prognostic biomarker. However, the prognostic significance of OPN expression in CCA is still controversial. We therefore immunohistochemically studied OPN expression in 354 resected CCAs and correlated the results with patient clinicopathological parameters. OPN expression was separately scored according to the percentage of cancer cells or degree of stromal tissue staining and classified as low (score 0-1) and high (score 2-3). OPN expression in CCA cells was found in 177 out of 354 patients (56.5%), whereas stroma was positive in 185 out of 354 patients (52.3%). Univariate analysis with several of the aforementioned parameters revealed that stromal but not cancer cell OPN expression was significantly associated with tumor size, tumor direct invasion into normal liver parenchyma, regional lymph node metastasis and higher staging. The combination of cancer cell and stromal OPN expression demonstrated a positive trend for linkage with lymph node metastasis. Multivariate analysis identified gender, the presence of lymphatic permeation and lymph node metastasis, but not OPN expression, as independent prognostic factors. This study confirms the presence of stromal OPN expression in tumor aggressiveness but not survival in CCA patients.

Zhang YH, Wang JJ, Li M, et al.
Matrix Metallopeptidase 14 Plays an Important Role in Regulating Tumorigenic Gene Expression and Invasion Ability of HeLa Cells.
Int J Gynecol Cancer. 2016; 26(3):600-6 [PubMed] Related Publications
OBJECTIVES: The objectives of this study were to investigate the functional effect of matrix metallopeptidase 14 (MMP14) on cell invasion in cervical cancer cells (HeLa line) and to study the underlying molecular mechanisms.
METHODS: Expression vector of short hairpin RNA targeting MMP14 was treated in HeLa cells, and then, transfection efficiency was verified by a florescence microscope. Transwell assay was used to investigate cell invasion ability in HeLa cells. Quantitative polymerase chain reaction and Western blotting analysis were used to detect the expression of MMP14 and relative factors in messenger RNA and protein levels, respectively.
RESULTS: Matrix metallopeptidase 14 short hairpin RNA expression vector transfection obviously decreased MMP14 expression in messenger RNA and protein levels. Down-regulation of MMP14 suppressed invasion ability of HeLa cells and reduced transforming growth factor β1 and vascular endothelial growth factor B expressions. Furthermore, MMP14 knockdown decreased bone sialoprotein and enhanced forkhead box protein L2 expression in both RNA and protein levels.
CONCLUSION: Matrix metallopeptidase 14 plays an important role in regulating invasion of HeLa cells. Matrix metallopeptidase 14 knockdown contributes to attenuating the malignant phenotype of cervical cancer cell.

Mauri G, Jachetti E, Comuzzi B, et al.
Genetic deletion of osteopontin in TRAMP mice skews prostate carcinogenesis from adenocarcinoma to aggressive human-like neuroendocrine cancers.
Oncotarget. 2016; 7(4):3905-20 [PubMed] Free Access to Full Article Related Publications
Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN-/-) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN-/- TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors.

Huang QX, Cui JY, Ma H, et al.
Screening of potential biomarkers for cholangiocarcinoma by integrated analysis of microarray data sets.
Cancer Gene Ther. 2016 Feb-Mar; 23(2-3):48-53 [PubMed] Related Publications
Cholangiocarcinoma (CCA) continues to harbor a difficult prognosis and it is difficult to diagnose in its early stages. The molecular mechanisms of CCA oncogenesis and progression are poorly understood. This study aimed to identify candidate biomarkers for CCA. Integrated analysis of microarray data sets was performed to identify differentially expressed genes (DEGs) between CCA and normal tissues. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed to identify the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. The expressions of DEGs were validated in human CCA tissues by qRT-PCR. A set of 712 DEGs were identified in CCA compared with normal tissues, including 306 upregulated and 406 downregulated DEGs. It can be shown from the KEGG pathway analysis that some pathways may have important roles in pathology of CCA, including peroxisome proliferator-activated receptor signaling pathway, bile secretion, cell cycle, fat digestion and absorption. PPI network indicated that the significant hub proteins were PKM, SPP1 and TPM1. The abnormally overexpression PKM, SPP1 and TPM1 were closely related to oncogenesis and progression of CCA. PKM, SPP1, TPM1, COL1A1 and COL1A2 may serve as candidate biomarkers for diagnosis and prognosis of CCA.

Inagaki Y, Shiraki K, Sugimoto K, et al.
Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity.
Int J Oncol. 2016; 48(2):533-40 [PubMed] Related Publications
Altered epigenetic control of gene expression plays a substantial role in tumor development and progression. Accumulating studies suggest that somatic mutations of CREB binding proteins (CBP)/p300 occur in some cancer cells. CBP/p300 possess histone acetyltransferase (HAT) activity, and are involved in many cellular processes. In this study, we investigated the expression and functional role of CBP/p300 in hepatocellular carcinoma (HCC) using the specific inhibitor C646 of CBP/p300 HAT activity. We examined its effect on several apoptosis-related proteins and invasion-related genes. The results showed that CBP/p300 were highly expressed in HCC tissues and that expression of p300, but not of CBP, was strongly correlated with the malignant character of HCC. C646 inhibited proliferation of HCC cell lines in a dose dependent manner. C646 significantly augmented TRAIL-induced apoptotic sensitivity, which was accompanied by reduced levels of survivin, in HepG2, HLE and SK-HEP1 cells. C646 significantly inhibited invasion of Huh7, HLE and SK-HEP1 cells. The level of matrix metallopeptidase 15 (MMP15) mRNA expression was significantly reduced, whereas the level of laminin alpha 3 (LAMA3) and secreted phosphoprotein 1 (SPP1) mRNA expression was significantly increased in Huh7 cells following exposure to C646. In conclusion, our results suggest that CBP/p300 HAT activity has an important role in malignant transformation, proliferation, apoptotic sensitivity and invasion in HCC. CBP/p300 could be a promising therapeutic target in HCC.

Tiwari A, Swamy S, Gopinath KS, Kumar A
Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo.
Sci Rep. 2015; 5:17621 [PubMed] Free Access to Full Article Related Publications
The ESRRA gene encodes a transcription factor and regulates several genes, such as WNT11 and OPN, involved in tumorigenesis. It is upregulated in several cancers, including OSCC. We have previously shown that the tumor suppressor miR-125a targets ESRRA, and its downregulation causes upregulation of ESRRA in OSCC. Upregulation of ESRRA in the absence of downregulation of miR-125a in a subset of OSCC samples suggests the involvement of an alternative mechanism. Using TaqMan(®) copy number assay, here we report for the first time that the genomic amplification of ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage-independent cell growth and invasion, and inhibited apoptosis. Whereas, knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage-independent cell growth and invasion, and accelerated apoptosis. Furthermore, the delivery of a synthetic biostable ESRRA siRNA to OSCC cells resulted in regression of xenografts in nude mice. Thus, the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers.

Song K, Liu N, Yang Y, Qiu X
Regulation of osteosarcoma cell invasion through osteopontin modification by miR-4262.
Tumour Biol. 2016; 37(5):6493-9 [PubMed] Related Publications
Osteopontin (OPN) is a phosphorylated glycoprotein that plays a critical role in the invasion of osteosarcoma (OS), the most common primary malignant bone tumor. Since microRNAs (miRNAs) have been well documented as key players in the tumorigenesis, cancer cell growth, and metastases, determination of the involved miRNAs that may regulate OPN-mediated OS cell invasion appears to be one important question in the current understanding and therapeutic strategies for OS. Here, we found that the levels of miR-4262 were significantly decreased and the levels of OPN were significantly increased in OS specimens, compared to the paired adjacent non-tumor tissue. Moreover, miR-4262 and OPN inversely correlated in OS specimens. The 5-year survival of the patients with lower miR-4262 levels in the resected OS was worse than that of patients with high miR-4262 levels. Bioinformatics analyses showed that miR-4262 targeted the 3'-UTR of OPN mRNA to inhibit its translation, which was proved by luciferase reporter assay. Furthermore, miR-4262 overexpression inhibited OPN-mediated cell invasion, while miR-4262 depletion increased OPN-mediated cell invasion in OS cells, in both a transwell cell invasion assay and a scratch wound healing assay. Together, our data suggest that suppression of miR-4262 in OS cells may promote OPN-mediated cancer invasion, highlighting miR-4262 as an intriguing therapeutic target to prevent OS metastases.

Lin F, Huang CM, Cao J, et al.
Segment-specific targeting via RNA interference mediates down-regulation of OPN expression in hepatocellular carcinoma cells.
Genet Mol Res. 2015; 14(4):14440-7 [PubMed] Related Publications
Osteopontin (OPN) plays an important role in the metastasis and recurrence of tumors after resection of hepatocellular carcinoma (HCC). In this study, the down-regulation effect on OPN expression in HCC cells of RNA interference (RNAi) molecules designed to target different segments of OPN was investigated to identify a more effective site for OPN knockdown. Specific small interfering RNAs (siRNAs A, B, and C) of OPN were synthesized and transfected into an HCC cell line (HEP-G2; representing the OPNi-A, OPNi-B, and OPNi-C groups). Fluorescent quantitative polymerase chain reaction and immunohistochemical methods were used to detect the mRNA and protein expression of OPN before and after RNAi. Results showed that after transfection, the fluorescence intensity of the OPNi-A group was greater than those of the OPNi-B and OPNi-C groups. After 48 h of transfection, the ΔCT values of OPN mRNA expression in the OPNi-A-C groups increased from 8.31 ± 1.58, 8.78 ± 1.49, and 8.25 ± 1.51 to 12.14 ± 1.43, 10.22 ± 1.97, and 10.48 ± 1.88, respectively (P < 0.05), and the OPN protein levels (immunohistochemistry scores) decreased from 6.44 ± 1.67, 5.43 ± 2.05, and 5.45 ± 2.52 to 2.84 ± 1.52, 4.43 ± 1.65, and 3.95 ± 1.43 points, respectively. These results indicated that RNAi based on different segments of the OPN gene had different down-regulatory effects on OPN expression. Synthesis of targeted siRNA aimed at specific OPN segments might have important significance for dealing with the invasiveness and metastasis of HCC cells.

Kopp S, Warnke E, Wehland M, et al.
Mechanisms of three-dimensional growth of thyroid cells during long-term simulated microgravity.
Sci Rep. 2015; 5:16691 [PubMed] Free Access to Full Article Related Publications
Three-dimensional multicellular spheroids (MCS) of human cells are important in cancer research. We investigated possible mechanisms of MCS formation of thyroid cells. Both, normal Nthy-ori 3-1 thyroid cells and the poorly differentiated follicular thyroid cancer cells FTC-133 formed MCS within 7 and 14 days of culturing on a Random Positioning Machine (RPM), while a part of the cells continued to grow adherently in each culture. The FTC-133 cancer cells formed larger and numerous MCS than the normal cells. In order to explain the different behaviour, we analyzed the gene expression of IL6, IL7, IL8, IL17, OPN, NGAL, VEGFA and enzymes associated cytoskeletal or membrane proteins (ACTB, TUBB, PFN1, CPNE1, TGM2, CD44, FLT1, FLK1, PKB, PKC, ERK1/2, Casp9, Col1A1) as well as the amount of secreted proteins (IL-6, IL-7, IL-8, IL-17, OPN, NGAL, VEGFA). Several of these components changed during RPM-exposure in each cell line. Striking differences between normal and malignant cells were observed in regards to the expression of genes of NGAL, VEGFA, OPN, IL6 and IL17 and to the secretion of VEGFA, IL-17, and IL-6. These results suggest several gravi-sensitive growth or angiogenesis factors being involved in 3D formation of thyroid cells cultured under simulated microgravity.

Azevedo FV, Lopes DS, Cirilo Gimenes SN, et al.
Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA₂ homologue from Bothrops pauloensis venom.
Int J Biol Macromol. 2016; 82:671-7 [PubMed] Related Publications
This work shows the antitumoral effects of BnSP-6, a Lys 49 PLA2 isolated from Bothrops pauloensis venom, on human breast cancer MDA-MB-231 cells. BnSP-6 caused a dose-dependent cytotoxicity and inhibited cell adhesion. Interestingly, cytotoxic activity of BnSP-6 was significantly lower against MCF10A, a non-tumorigenic breast cell line, suggesting that this PLA2 presented a possible preference for targets in cancer cells. Analysis of cell death on MDA-MB-231 cells showed that BnSP-6 stimulated the autophagy process, as evidenced by labeling of autophagic vacuoles. Moreover, apoptosis assays showed that BnSP-6 induced both early and late apoptosis. Apoptosis of MDA-MB-231 cells was also confirmed by up-regulation of different genes related to the apoptosis pathway, such as TNF, TNFRSF10B, TNFRSF1A and CASP8 and decreased expression of anti-apoptotic genes (BCL2 and BCL2L). In addition, BnSP-6 caused a remarkable increase in gene expression of BRCA2 and TP53 tumor suppressors. Finally, BnSP-6 induced down-regulation of Angiopoetin 1 gene (potent pro-angiogenic factor) and inhibited adhesion and migration of MDA-MB-231 cells suggesting pharmaceutical applications of this PLA2 as an antiangiogenic and anti-metastatic agent. Taken together, our results show that the PLA2 BnSP-6 presents anticancer potential that can be exploited as prototype for the design of new therapies.

Chimparlee N, Chuaypen N, Khlaiphuengsin A, et al.
Diagnostic and Prognostic Roles of Serum Osteopontin and Osteopontin Promoter Polymorphisms in Hepatitis B-related Hepatocellular Carcinoma.
Asian Pac J Cancer Prev. 2015; 16(16):7211-7 [PubMed] Related Publications
BACKGROUND: The aims of this study were to evaluate the diagnostic and prognostic roles of serum osteopontin (OPN) and single nucleotide polymorphisms (SNPs) in the OPN promoter in patients with hepatitis B-related hepatocellular carcinoma (HCC).
MATERIALS AND METHODS: Four groups were studied, which included 157 patients with HCC, 73 with liver cirrhosis (LC) and 97 with chronic hepatitis (CH), along with 80 healthy subjects. Serum OPN and alpha-fetoprotein (AFP) levels were measured. The SNPs -66 T/G, -156 G/δG and -433 C/T within the OPN promoter were determined by direct sequencing.
RESULTS: Serum OPN levels were significantly higher in patients with HCC than in the other groups. Area under receiver operating characteristics curves in distinguishing HCC from chronic liver disease (CLD; CH and LC) were 0.782 (95% CI; 0.729-0.834) for OPN and 0.888 (95% CI; 0.850-0.927) for AFP. Using the optimal cut-off value (70 ng/mL), OPN had sensitivity and specificity of 72% and 71%, respectively. Serum OPN was superior to AFP in detecting early-stage HCC (68% vs. 46%). A combination of both markers yielded an improved sensitivity for detecting early HCC to 82%. A high OPN level was significantly correlated with advanced BCLC stage and was an independent prognostic factor for HCC. The SNPs -156 and -443 were associated with susceptibility to HCC, but were not related to overall survival.
CONCLUSIONS: Serum OPN is a useful diagnostic and prognostic marker for HCC. The combined use of serum OPN and AFP improved the diagnosis of early HCC. Genetic variation in the OPN promoter is associated with the risk, but not the prognosis of HCC.

Luo SD, Chen YJ, Liu CT, et al.
Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma.
Biomed Res Int. 2015; 2015:508587 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteopontin (OPN) is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC) in humans has not yet been investigated.
METHODS: We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients' biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin.
RESULTS: Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF). An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin.
CONCLUSIONS: A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT.

Leitner L, Jürets A, Itariu BK, et al.
Osteopontin promotes aromatase expression and estradiol production in human adipocytes.
Breast Cancer Res Treat. 2015; 154(1):63-9 [PubMed] Related Publications
Breast and endometrial cancer are often estrogen dependent, and their incidence and mortality are increased by obesity in postmenopausal women. Osteopontin (OPN) is a cytokine strongly upregulated in adipose tissue (AT) in obesity. OPN function is potentiated by cleavage by matrix metalloproteinases (MMP). OPN and MMPs play a role in cancer development and are prognostic markers in breast cancer progression. While induction of the estrogen-synthesizing enzyme aromatase by TNFa and IL1 has been shown in preadipocytes, an impact of OPN on aromatase expression in AT has not been investigated yet. Gene expression was determined in AT samples of 21 morbidly obese and matched non-obese subjects. Primary human adipocytes were treated with full-length OPN or MMP-cleaved OPN (cOPN). Protein and mRNA expressions were analyzed from cell lysates, or cells were subsequently supplied with testosterone to determine estradiol production and for indirect co-culture with the estrogen-dependent MCF-7 cell line. Aromatase expression strongly correlated with gene expression of OPN and various MMPs in visceral and MMPs in subcutaneous AT, but not with TNFα expression in both tissues. In vitro, cOPN more effectively than full-length OPN upregulated aromatase mRNA in adipocytes and significantly increased aromatase protein level and estradiol production, leading to increased MCF-7 growth in indirect co-culture. OPN and MMPs are upregulated in AT in obesity, and MMP-cleaved OPN is particularly effective in inducing aromatase activity in human adipocytes. Thereby, obesity-induced OPN expression in AT may contribute to estradiol production and thus to the association of obesity with estrogen-dependent cancers.

Gerke TA, Martin NE, Ding Z, et al.
Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.
Prostate. 2015; 75(16):1926-33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer.
METHODS: Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; n = 276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; n = 347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays.
RESULTS: During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up.
CONCLUSIONS: Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research.

Lee SH, Park JW, Go DM, et al.
Ablation of osteopontin suppresses N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric cancer development in mice.
Carcinogenesis. 2015; 36(12):1550-60 [PubMed] Related Publications
Several clinical studies have reported increased expression of osteopontin (OPN) in various types of human cancer, including gastric cancer. However, the precise mechanisms underlying tumor development remain unclear. In the present study, we investigated the pathogenic roles of OPN in Helicobacter pylori-induced gastric cancer development. Wild-type (WT) and OPN knockout (KO) mice were treated with N-methyl-N-nitrosourea (MNU) and infected with H.pylori. Mice were killed 50 weeks after treatment, and stomach tissues were assessed by histopathological examination, immunohistochemistry, quantitative real-time RT-PCR and western blotting. To clarify the carcinogenic effects of OPN, we also conducted an in vitro study using AGS human gastric cancer cell line and THP-1 human monocytic cell line. The overall incidence of gastric tumors was significantly decreased in OPN KO mice compared with WT mice. Apoptotic cell death was significantly enhanced in OPN KO mice and was accompanied by upregulation of signal transducer and activator of transcription 1 (STAT1) and inducible nitric oxide synthase (iNOS). In vitro study, OPN suppression also caused STAT1 upregulation and iNOS overexpression in AGS and THP-1 cells, which resulted in apoptosis of AGS cells. In addition, a negative correlation was clearly identified between expression of OPN and iNOS in human gastric cancer tissues. Our data demonstrate that loss of OPN decreases H.pylori-induced gastric carcinogenesis by suppressing proinflammatory immune response and augmenting STAT1 and iNOS-mediated apoptosis of gastric epithelial cells. An important implication of these findings is that OPN actually contributes to the development of gastric cancer.

Ding K, Fan L, Chen S, et al.
Overexpression of osteopontin promotes resistance to cisplatin treatment in HCC.
Oncol Rep. 2015; 34(6):3297-303 [PubMed] Related Publications
Osteopontin (OPN) is a multi-functional cytokine involved in cell survival, migration and adhesion. Increasing evidence has elucidated its role in tumorigenesis, progression and metastasis. However, the role of OPN in chemoresistance of human hepatocellular carcinoma (HCC) has not yet been clarified. In the present study, we examined the expression of OPN in human HCC samples before and after cisplatin-treatment, the results showed that OPN was significantly increased in cisplatin-resistant specimens. We then studied the effect of cisplatin on OPN expression in HCC cells, after exposure to cisplatin, the expression of OPN in HCC cells was elevated compared to control cells. We also found that PI3K/AKT signaling pathway was also activated by cisplatin and this effect was induced by the OPN pathway. To study the effect of OPN on chemoresistance, HCC cells were treated with cisplatin along with OPN. Incubation with OPN enchanced the chemoresistance of HCC cells to cisplatin. In contrast, blockage of OPN pathway promoted the chemosensitivity of HCC cells to cisplatin. Our results suggest that OPN enhanced chemoresistance of cisplatin in HCC cells by activating PI3K/AKT signaling pathway, blocking the OPN pathway might be a novel way to overcome the disease.

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