Abstract. Human osteopontin (OPN) is a glycosylated phosphoprotein which is expressed in a variety of tissues in the body. In recent years, accumulating evidence has indicated that the aberrant expression of OPN is closely associated with tumourigensis, progression and most prominently with metastasis in several tumour types. In this review, we present the current knowledge on the expression profiles of OPN and its main splice variants in human cancers, as well as the potential implications in patient outcome. We also discuss its putative clinical application as a cancer biomarker and as a therapeutic target. IntroductionOsteopontin (OPN) is a bone associated, extracellular matrix glycosylated phosphoprotein which is produced by several cell types, including osteoblasts, osteoclasts, immune cells, endothelial cells, epithelial cells and extra-osseous cells (skin, kidney and lung) (1-3). Due to differences in post-translational modification (PTM) (phosphorylation, glycosylation, sulfation and proteolysis) from different cellular sources, OPN has a molecular weight ranging from 41 to 75 kDa, which may have a cell type-specific structure and function (4-7). OPN plays a major role in various normal physiological processes, including bone remodelling, immune-regulation, inflammation and vascularisation (8,9). In addition, OPN has also been shown to be involved in carcinogenesis with multi-functional activities (10)(11)(12).OPN is involved in a series of biological functions through interactions with different integrins and CD44. Therefore, OPN is classified as a member of the ʻsmall integrin-binding ligand N-linked glycoproteins' (SIBLINGs) together with other molecules, including bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE) (13). Two critical integrin binding sequences of OPN have been identified: arginine-glycine-aspartic acid (RGD) and serine-valine-valinetyrosine-glutamate-leucine-arginine (SVVYGLR). OPN interacts mainly with various αv (particularly αvβ1, αvβ3, αvβ5) integrin receptors via the classical RGD sequence, and interacts with α9β1, α4β1, α4β7 via SVVYGLR (14-16). In addition, it also interacts with the CD44 splice variants, CD44v3, CD44v6 and CD44v7, via the C-terminal fragment calcium binding site (17)(18)(19)(20). These properties of OPN induce the activation of signal transduction pathways, leading to cell proliferation, adhesion, invasion and migration, which have been demonstrated by both in vitro and in vivo models (21-23). The binding of OPN to integrins and CD44 initiates a downstream signalling cascade via the PI3K/AKT signalling pathway leading to NF-κB mediated cell proliferation and survival (24)(25)(26). In additon, through the Ras/Raf/MEK/ERK signalling pathway, an OPN-integrin complex and subsequent induction of AP-1-dependent gene expression, urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) confer a metastatic phenotype on some cancer cell types (27)(28)(29...