Abstract 417: Inflammation initiates OCT4/NANOG expression through IL-6-IGF-1R signaling activation and is associated with early recurrence of HBV-related HCC

Abstract

Abstract Inflammatory microenvironment is a well-known promoter of hepatocellular carcinoma (HCC), a cancer with high rates of postoperative recurrence and poor prognosis. However, mechanisms underlying the inflammation-induced HCC promotion remain largely unknown. Here we demonstrate the effect of proinflammatory cytokine IL6 on IGF-1R signaling activation which initiates OCT4/NANOG expression and is associated with HBV-related HCC (HBV-HCC) recurrence. In this study, real-time quantitative PCR analysis demonstrated a high correlation between IGF-1R and OCT4/NANOG transcriptional expression in human HCC frozen tissues (N=119, R=0.8097 for OCT4; R= 0.8375 for NANOG). Interestingly, the OCT4, NANOG, or IGF-1R level in HBV-HCC was significantly higher than that in non HBV-HCC. Cultivation of cells in inflammation condition medium (Inflam-CM) increased OCT4/NANOG level in HBV+HBsAg+ cells (HepG2.2.15 and Hep3B), but not in HBV+HBsAg− (HA22T) or HBV−HBsAg− cells (HepG2 and Huh7). Epifluorescence/luciferase assay further demonstrated that Inflam-CM increased the GFP+ cell population as well as the luciferase activity of OCT4 promoter-GFP/luciferase-HepG2.2.15 cells. Besides, Inflam-CM significantly increased the IGF-1/IGF-1R transcriptional level and activated the IGF-1R signaling (phospho-IGF-1R and phospho-Akt) in HepG2.2.15 and Hep3B. Blockage of IGF-1R phosphorylation by picropodophyllin (PPP) dramatically decreased the OCT4/NANOG transcriptional activity. IL-6 stimulated the autocrinal IGF-I and IL-6 expression whereas AG490 (a phospho-STAT inhibitor) decreased the IGF-1R phosphorylation. The significant clinical association between early and overall postoperative recurrence and IGF-1R/OCT4/NANOG expression in both gene (real time RT-PCR) and protein (immunohistochemical staining) levels were demonstrated. When etiologic differences were considered, HBV-positive patients have the trend towards early HCC recurrence. Conclusion: Niche inflammatory stress might activate an autocrinal IL-6-IGF-I/IGF-1R-Akt signaling and OCT4/NANOG expression which is associated with early HBV-HCC recurrence. These results provide potential targets for individualized adjuvant therapy for HBV-HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 417. doi:1538-7445.AM2012-417