Figure 7. Osteopontin (OPN) activates NF-κB signaling via a novel dual mechanism involving secretory OPN (sOPN) and intracellular OPN (iOPN).

sOPN induces NF-κB signaling by acting on cell surface receptors via an autocrine loop while iOPN activates NF-κB signaling by transcriptionally downregulating A20/TNFAIP3 and ABIN1/TNIP1. As A20 and ABIN1 are negative regulators responsible for terminating and limiting NF-κB signaling, their downregulation would have an amplifying and prolonging effect on NF-κB signaling by other inducers including sOPN. Our data show that OPN-induced activation of NF-κB results in increased tumor growth and activation of MMP8 leading to tumor invasion and dissemination.