Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Tilli, Tatiana Martins; Franco, Vanessa Ferreira; Robbs, Bruno Kaufmann; Wanderley, João Luiz Mendes; Silva, Fabrício Ribeiro de Azevedo da; Mello, Kivvi Duarte de; Viola, João P. B.; Weber, Georg F.; Gimba, Etel Rodrigues Pereira

doi:10.1158/1541-7786.mcr-10-0463

Cited by 80 publications

(90 citation statements)

References 49 publications

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“…However, OPN-c expression dramatically reduced cell adhesion, and the authors suggest that OPN isoforms have distinct effects on cell behaviour but can work together to promote EAC progression (60). This is consistent with the clinical evidence described above suggesting that both OPN-b and OPN-c are overexpressed in some cancers, for example pancreatic (69,74), gastric (70), lung (74), and prostate (73), while OPN-c may be most strongly associated with other cancers, such as breast cancer (64,74,75) and ovarian cancer (76).…”

Section: Osteopontin Splice Variantsevidence For Association With Spesupporting

confidence: 77%

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

Viloria

Hill

2016

Biomolecular Concepts

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

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Section: Osteopontin Splice Variantsevidence For Association With Spesupporting

confidence: 77%

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

Viloria

Hill

2016

Biomolecular Concepts

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“…18 Recently, Tilli and colleagues demonstrated that the isoform OPN-c is specifically expressed in ovarian tumor samples and significantly activates OvCar-3 cell proliferation, migration, invasion, anchorageindependent growth and tumor formation in vivo. 19 These results demonstrate that different OPN transcripts have distinct roles that may be associated with their distinct roles in host defense and tumor process. Whether OPN transcripts have different roles in breast cancer formation in vivo and whether OPN transcripts expressed by tumor cells have distinct functions on immune cell differentiation are unknown.…”

Section: Introductionmentioning

confidence: 79%

“…Most recently, it has been reported that OPN-c specifically activated ovarian tumor cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. 19 With consideration of the high level of OPN expressed by tumor cells, we constructed lentiviral expression vectors driven by a strong constitutive promoter and compared the function of all three OPN transcripts in breast cancer in vivo. We found that the overexpression of OPN transcripts significantly induced tumor growth possibly by promoting proliferation and preventing apoptosis of tumor cells; however, there was no significant difference among the three transcripts.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Sun¹,

Feng²,

Chen³

et al. 2013

Cell Mol Immunol

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Osteopontin (OPN), a multifunctional glycoprotein, has three transcripts that have distinct roles in tumors in vitro. Whether OPN transcripts have different functions in tumor processes in vivo is unclear. It has been reported that immune cell-derived OPN can promote tumor formation. We propose a hypothesis that tumor-derived OPN may facilitate tumor immune escape by affecting immune cell differentiation and function. In this study, we constructed lentiviral expression vectors of OPN transcripts and transfected them into the MCF-7 cell line. MCF-7 cells transfected with OPN transcripts were injected into the armpit of nude mice, and tumor growth was monitored. The results showed that all OPN transcripts promoted local tumor formation, but that there was no significant difference among transcripts. We also investigated the effect of the OPN expressed by tumor cells on monocyte differentiation by coculturing monocytes with tumor supernatant. We found OPN-c upregulated CD163 levels compared with OPN-a and OPN-b; however, none of the transcripts affected HLA-DR and CD206 levels. All OPN transcripts significantly inhibited TNF-a and enhanced IL-10 production by monocytes. Furthermore, we found that the overexpression of OPN transcripts significantly upregulated TGF-b1 and MCP-1 production by tumor cells. Using neutralizing antibody and recombinant cytokines, we found that OPN overexpressed by tumor cells regulates the production of TNF-a and IL-10 by monocytes partly via MCP-1 and TGF-b1, respectively. Collectively, our results show that OPN transcripts have no distinct role in breast cancer formation in vivo. We also demonstrate that OPN regulates the alternative activation of monocytes via TGF-b1 and MCP-1, which may represent an additional mechanism for tumor immune escape.

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“…OPN mRNA and/or protein expression levels were reported to be increased in several types of human cancers, such as prostate carcinoma (11); melanoma (12); and ovary (13), lung and gastric carcinoma (14). OPN overexpression was associated with poor prognosis in some malignancies, namely, in PTC (15).…”

Section: Introductionmentioning

confidence: 99%

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

Ferreira¹,

Eloy²,

Pestana³

et al. 2016

European Journal of Endocrinology

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Background: Osteopontin (OPN) or secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and has been shown to be involved in tumourigenesis and metastasis in many malignancies, including follicular cell-derived thyroid carcinomas. Its role in C-cell-derived thyroid lesions and tumours remains to be established. Objective: The objective of this study is to clarify the role of OPN expression in the development of medullary thyroid carcinoma (MTC). Methods: OPN expression was analysed in a series of 116 MTCs by immunohistochemistry and by qPCR mRNA quantification of the 3 OPN isoforms (OPNa, OPNb and OPNc) in six cases from which fresh frozen tissue was available. Statistical tests were used to evaluate the relationship of OPN expression and the clinicopathological and molecular characteristics of patients and tumours. Results: OPN expression was detected in 91 of 116 (78.4%) of the MTC. We also observed high OPN expression in C-cell hyperplasia as well as in C-cells scattered in the thyroid parenchyma adjacent to the tumours. OPN expression was significantly associated with smaller tumour size, PTEN nuclear expression and RAS status, and suggestively associated with non-invasive tumours. OPNa isoform was expressed significantly at higher levels in tumours than in non-tumour samples. OPNb and OPNc presented similar levels of expression in all samples. Furthermore, OPNa isoform overexpression was significantly associated with reduced growth and viability in the MTC-derived cell line (TT). Conclusion: The expression of OPN in normal C-cells and C-cell hyperplasia suggests that OPN is a differentiation marker of C-cells, rather than a marker of biological aggressiveness in this setting. At variance with other cancers, OPN expression is associated with good prognostic features in MTC.

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Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Cited by 80 publications

References 49 publications

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

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

Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma

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