The secreted glycol-
phosphoprotein OPN not only plays important roles in immune responses and tissue remodeling but is also intimately involved in
tumorigenesis. It is up-regulated in various
cancers and correlated with poor prognosis. It is evident by enhancing growth and migration of
cancer cells. However, the mechanisms that participate in up-regulation of OPN in
lung cancer are largely unknown. Up-regulation of
aryl hydrocarbon receptor (AhR), a
transcription factor activated by
xenobiotics, has been observed in
lung cancer as well as premalignant lesions. In this study we demonstrated that AhR positively regulates OPN expression in
lung cancer. We observed positive correlation of OPN and AhR expression in
lung cancer specimen. Knockdown or overexpression of AhR exhibited down- or up-regulation of OPN expression in
lung cancer cells. We identified an OPN promoter region between positions -268 and +435 that was activated by both
ligand-independent and
ligand-activated AhR. However, this region does not contain AhR response element/
dioxin response element (DRE/XRE). Further truncations and internal deletions of the promoter revealed that the
ligand-independent and
ligand-activated AhR function through different regions of OPN promoter. The region between -268 and -100 was required for
ligand-independent AhR activity. This region contains several cis-elements including AP2, C/EBP, SP1 and AP1 sites. On the other hand, the
ligand-activated AhR up-regulates OPN activity through two regions of OPN promoter; one contains NFκB site at +137 and the other is between positions -100 and +126. This study suggested that both overexpression of un-induced AhR (in cases of non-smokers with high level of AhR) and
ligand-activated AhR (such as smokers) contribute to up-regulation of OPN that in turn leads to lung
tumorigenesis.