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Role of osteopontin in the pathophysiology of cancer.

ABSTRACT: Osteopontin (OPN) is a multifunctional cytokine that impacts cell proliferation, survival, drug resistance, invasion, and stem like behavior. Due to its critical involvement in regulating cellular functions, its aberrant expression and/or splicing is functionally responsible for undesirable alterations in disease pathologies, specifically cancer. It is implicated in promoting invasive and metastatic progression of many carcinomas. Due to its autocrine and paracrine activities OPN has been shown to be a crucial mediator of cellular cross talk and an influential factor in the tumor microenvironment. OPN has been implicated as a prognostic and diagnostic marker for several cancer types. It has also been explored as a possible target for treatment. In this article we hope to provide a broad perspective on the importance of OPN in the pathophysiology of cancer.

SUBMITTER: Shevde LA

PROVIDER: S-EPMC5916777 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Role of osteopontin in the pathophysiology of cancer.

Shevde Lalita A LA Samant Rajeev S RS

Matrix biology : journal of the International Society for Matrix Biology 20140319

Osteopontin (OPN) is a multifunctional cytokine that impacts cell proliferation, survival, drug resistance, invasion, and stem like behavior. Due to its critical involvement in regulating cellular functions, its aberrant expression and/or splicing is functionally responsible for undesirable alterations in disease pathologies, specifically cancer. It is implicated in promoting invasive and metastatic progression of many carcinomas. Due to its autocrine and paracrine activities OPN has been shown ...[more]

PMID: 24657887

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Project description:Osteopontin (OPN), a multifunctional protein, has emerged as a potentially valuable biomarker for diagnosing and treating cancers. Recent research focuses on its involvement in tumor biology including the cell proliferation, survival, angiogenesis, invasion, and metastasis. Understanding the molecular mechanisms and pharmacological effects of OPN in cancer development could lead to new targets for improving cancer diagnosis and treatment. This review explains how the structurally conserved domains of OPN are associated with OPN signaling mediators and CD44, and how the conserved OPN domains determine biological functions. The authors have reviewed representative works of OPN expression in breast cancer and colorectal cancer to elucidate the relationship between OPN and cancer/tumor biology. It has also been shown that the prognostic sensitivity in non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, and ovarian cancer improved compared to the individual marker when OPN was analyzed in conjunction with other markers. The therapeutic approaches based on OPN inhibitors are discussed to illustrate recent research progress. Previous clinical data has indicated that OPN has played a unique role in cancer development, but further investigation is required to understand the underlying mechanism. More clinical trials are also required to examine the applicability and efficacy of OPN inhibitors in cancer therapy.

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Project description:INTRODUCTION:Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis among cancers, mainly due to the high incidence of early metastases. RAN small GTPase (RAN) is a protein that plays physiological roles in the regulation of nuclear transport and microtubule spindle assembly. RAN was recently shown to mediate the invasive functions of the prometastatic protein osteopontin (OPN) in breast cancer cells. We and others have shown previously that high levels of OPN are present in PDA. In this study, we analyzed the expression and correlation of RAN with OPN in human pancreatic lesions, and explored their regulation in PDA cell lines. METHODS:Real time PCR was used to analyze RAN and OPN mRNA levels in PDA, adjacent non-malignant, and benign pancreatic tissues. Expression levels were correlated with survival and different clinicopathological parameters using different statistical methods. Transient transfection studies using OPN and RAN plasmids, and knockdown experiments using siRNA were used to examine their mutual regulation. RESULTS:OPN and RAN levels highly correlated with each other (p<0.0001). OPN or RAN levels did not correlate with venous lymphatic invasion, diabetes, obesity, T stage, BMI, or survival. However, we found a significant association between RAN levels and perineural invasion (HR=0.79, 95% CI 0.59, 1.07; p=0.0378.). OPN and RAN colocalized in PDA tissues and cell lines. Increasing RAN expression in PDA cells induced OPN transcription and RAN silencing reduced total OPN levels. OPN did not have any significant effect on RAN transcription. CONCLUSIONS:The high levels of RAN in PDA and its correlation with OPN and with perineural invasion suggest that RAN may contribute to PDA metastasis and progression through the induction of OPN. RAN's role in the regulation of OPN in PDA is unique and could provide potential novel therapeutic strategies to combat PDA aggressiveness.

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Osteopontin in systemic sclerosis and its role in dermal fibrosis.

Project description:Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Here, we determined whether OPN levels are increased in a large cohort of patients with systemic sclerosis (SSc) and whether OPN contributes to the development of dermal fibrosis. The plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared with healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin (bleo)-induced dermal fibrosis model. OPN-deficient (OPN(-/-)) mice developed less dermal fibrosis compared with wild-type (WT) mice in the bleo-induced dermal fibrosis model. Additional in vivo studies have demonstrated that lesional skin from OPN(-/-)mice had fewer Mac-3-positive cells, fewer myofibroblasts, decreased transforming growth factor (TGF)-? and genes in the TGF-? pathway, and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and extracellular signal-regulated kinase. In vitro, OPN(-/-) dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGF-?. Finally, TGF-? production by OPN-deficient macrophages was reduced compared with WT. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that it may be a new therapeutic target in SSc.

| S-EPMC3365548 | biostudies-literature

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