Abstract 1792: Association of enhanced IGF-1R signaling and HBV/inflammation with poor HCC prognosis

Abstract

Abstract Hepatocellular cell carcinoma (HCC) associated with chronic HBV hepatitis tends to have a more unfavorable prognosis. Recently, a global transcriptome analysis by Boyault's group suggested that HBV infection would result in chromosome instability and activation of insulin-like growth factor receptor (IGFR)/AKT signaling pathway (but not the β-catenin pathway) of a subgroup of HCC. As both chronic inflammation and viral infection have been demonstrated to be important promoters for HCC tumorigenesis, we investigated the potential effects of HBV and chronic inflammation on the activation of IGF signaling pathway. By using the paired HBV- positive and HBV-negative HCC cell lines (HepG2.2.15 (HBV+) vs. HepG2 (HBV-); and Hep3B (HBV+) vs. Huh7 (HBV-)), we found the increased expression of IGF1 receptor at both gene (by RT PCR) and protein levels (by Western blotting) in HBV-positive HCC cell lines. Meanwhile, the IGF-1R activation signaling (such as phospho-IGF-1R and phospho-Akt) was also significantly increased in HBV-positive HCC cell line (Hep3B vs. Huh7). To further examine the role of inflammatory cytokine(s) in IGF-1 signaling of HCC cells, increasing dilution folds of LPS (lipopolysaccharide)- stimulated monocyte-differentiated U937 cell condition medium (U937-CM) were added in culture medium for treatment of HepG2 and HepG2.2.15 cells. By Western blotting analysis, the chronic inflammation condition showed enhancement of the IGF-1R protein expression in the HepG2.2.15 while comparing with the HepG2 cells. These observations suggested that the inflammatory stress may further elevate the IGF-1R expression in HBV-positive HepG.2.2.15 cell line. The associated clinical implication was further evaluated by high throughput tissue microarray. Our results revealed a negative correlation between phospho-IGF-1R expression and disease-free survival. In summary, our work showed that both HBV and chronic inflammation promoted IGF-1R activation signaling which may result in the poor prognosis of a subgroup of HCCs. The underlying mechanism(s) contributing the IGF-1R-mediated signal to the ominous disease outcome still needs further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1792.