Abstract 1512: Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma

Abstract

Abstract Purpose: To unravel the role of inflammatory cytokine IL-6 and IGF-1 receptor (IGF-1R) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGF-1R in hepatocellular carcinoma (HCC). Experimental Design: Frozen liver and HCC tissue samples were obtained from 191 patients who received curative hepatectomy between 2004 and 2012. Serum levels of IL-6 were detected using ELISA assays (n = 120). The effects of IL-6/IGF-1 on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGF-1 receptor (p-IGF-1R) in tissues were detected by western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGF-1R expression levels in tissues (n = 191) were analyzed by real-time Q-PCR and was correlated with early tumor recurrence using Kaplan-Meier survival analysis. Results: A high positive correlation between the expression levels of OCT4/NANOG and IGF-1R/p-IGF-1R in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-1R was mostly confined to HBV-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL-6 were significantly correlated with high OCT4/NANOG expression. IL-6 stimulated an autocrine IGF-1/IGF-1R expression STAT3-dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGF-1R activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL-6-induced stemness-related properties both in vitro and in vivo. Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL-6-induced IGF/IGF-1R activation, particularly in HBV-HCC. Citation Format: Te-Sheng Chang, Yu-Chih Wu, Ying-Huang Tsai, Yen-Hua Huang. Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1512. doi:10.1158/1538-7445.AM2015-1512