Intracellular Osteopontin Inhibits Toll-Like Receptor Signaling And Impedes Liver Carcinogenesis

Osteopontin (OPN) has been implicated widely in tumor growth and metastasis, but the range of its contributions is not yet fully understood. In this study, we showthat genetic ablation of Opn in mice sensitizes themto diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Opn-deficientmice (Opn(-/-) mice) exhibited enhanced production of proinflammatory cytokines and compensatory proliferation. Administering OPNantibody or recombinant OPN protein to wild-type or Opn(-/-) mice-derived macrophages, respectively, had little effect on cytokine production. In contrast, overexpression of intracellular OPN (iOPN) in Opn-deficient macrophages strongly suppressed production of proinflammatory cytokines. In addition, we found that iOPN was able to interact with the pivotal Toll-like receptor (TLR) signaling protein MyD88 in macrophages after stimulation with cellular debris, thereby disrupting TLR signaling in macrophages. Our results indicated that iOPN was capable of functioning as an endogenous negative regulator of TLR-mediated immune responses, acting toameliorate production of proinflammatory cytokines and curtail DEN-induced hepatocarcinogenesis. Together, our results expand the important role of OPN in inflammation-associated cancers and deepen its relevance for novel treatment strategies in liver cancer. (C)2014 AACR.