Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis

Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte-derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome-based OPN correlation network was associated with HCC incidence along 10 years of follow-up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (Opn^Hep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (Opn^ΔHep) expressed a similar phenotype. The acute response to DEN was reduced in Opn^ΔHep, which also showed more cancer stem/progenitor cells (CSCs, CD44⁺AFP⁺) at 5 months. CSCs from Opn^Hep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from Opn^Hep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn^−/− compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44^−/−Opn^Hep Tg mice. Conclusions: Hepatocyte-derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro-tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation.