MWC: Research planning, BV-6 nmr statistical analysis, manuscript drafting. LX: Research planning, surgery and maintenance of patients’ database. LD: RT-PCR operations. GYM: RT-PCR operations, data sorting and processing. MHL: Patients’ data sorting and processing. All authors read and approved the final manuscript.”
“Introduction OPN is a multifunctional protein involved in several pathological processes such as inflammation and cancer [1]. As an acidic glycophosphoprotein, OPN contains a RGD (arginine-glycine-aspartate) integrin binding motif, a hydrophobic

leader sequence (indicative of its secretory characteristic), a thrombin cleavage site adjacent to RGD domain, and a cell attachment sequence [2]. OPN has been found to be present in three forms in tissues and fluids: i) an intracellular protein in complex with hyaluronan-CD44-ERM (ezrin/radixin/moesin) that is involved in migration of tumor and stromal cells [3]; ii) an extracellular protein that is abundant at mineralized tissues [4]; iii) a secreted protein that is found in fluids isolated from metastatic tumors [5] and also found in organs such as placenta [6, 7], breast [8], and testes [9]. At the protein synthesis level, OPN undergoes extensive post-translational modification including phosphorylation

and see more glycosylation [10]. Additionally, there are three splice variants of OPN (OPNa, OPNb, and OPNc) that may have distinct characteristics in different tissues and tumor types [11]. For example, OPN-c has been BIX 1294 concentration suggested

to be expressed in invasive breast tumors and is highly correlated with patient’s survival in HER-2 breast patients [12]. Irrespective of OPN isoform, a series of other studies have suggested a role for plasma CYTH4 OPN as a biomarker of tumor progression in colon [13, 14], lung [15], and prostate cancers [16, 17]. The RGD sequence in OPN protein enables it to bind to CD44-ERM and several integrins including αVβ1, αvβ3, and αVβ5 [18]. Given the wide expression of integrins and CD44, both cancer cells as well as stromal compartment are targeted by OPN in the tumor mass. Binding of OPN to the above receptors on tumor cells triggers downstream signaling pathways including Ras, Akt, MAPK, Src, FAK and NF-KB [1] that collectively lead to the following in tumor cells: i) invasion to ECM (extracellular matrix) mainly via upregulation of MMPs [19] (matrix metalloproteinases) and uPAs [20] (urokinase plasminogen activator) by OPN; ii) increased migration and adhesion of tumor cells [21]; iii) inhibition of cell death likely through upregulation of anti-apoptosis mediators such as GAS6 [22]; and iv) development of pre-metastatic niche [23]. Additionally, tumor stroma such as endothelial cells [18] and immune infiltrating cells [24, 25] (particularly monocytes) express OPN receptors.