Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer

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Abstract
Small integrin-binding ligand N-linked glycoproteins (SIBLINGs) are a family of glycophosphoproteins comprising osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE). The genes encoding the SIBLINGs are located within a cluster on chromosome 4 and encode soluble, hydrophilic proteins sharing common functional motifs and domains, including an Arg–Gly–Asp (RGD) motif that binds αvβ3 integrin. SIBLINGs were initially described as mineralized tissue-associated glycophosphoproteins and were thought to be functionally restricted to these tissues. Recent results show that they are more widely distributed and are expressed in non-mineralized normal tissue, such as metabolically active ductal epithelial cells. Some SIBLINGs activate specific metalloproteinases (MMPs; BSP activates MMP2, OPN, MMP3 and DMP1, MMP9). These three SIBLINGs also bind complement factor H and prevent complement attack. SIBLINGs are overexpressed in many cancers. OPN and, less so, BSP are by far the more widely studied to date and their levels of expression are correlated with tumour aggressiveness. SIBLINGs can be detected in the blood and their level of expression is associated with prognosis. Among SIBLINGs, OPN is involved in almost all steps of tumour progression, including invasion, metastasis and angiogenesis. In vitro and in vivo experimental models demonstrated that interference with SIBLINGs, such as small interfering RNA selective knockdown, has potential anticancer therapeutic value. Identifying the specific roles of SIBLINGs in cancer–stroma interactions and signalling cascades involving growth factor–growth factor receptor and cell–matrix interactions could result in the development of additional and refined strategies for the prevention and treatment of metastases.