Abstract
To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC). Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI 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-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis. A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo. The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third leading cause of cancer-related mortality worldwide [1]
The concurrent expression of octamer 4 (OCT4)/ NANOG/IGFI receptor (IGFIR) was mostly confined to hepatitis B virus (HBV)–related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence
This study shows that patients with hepatitis B virus (HBV)– related hepatocellular carcinoma (HBV-HCC) exhibit a high rate of concurrent expression of interleukin (IL)-6 in sera, and OCT4, NANOG, and insulin-like growth factor (IGF) I receptor-(IGFIR) in primary tumors
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third leading cause of cancer-related mortality worldwide [1]. Surgical resection can be curative in the early stages of HCC, but the risk of recurrence remains high. As tumor stemness properties are related to HCC recurrence [2], investigating the mechanisms responsible for the expression of tumor stemness could lead to strategies to prevent tumor recurrence and to improvements in the efficacy of HCC treatment. Clinical and epidemiologic studies have identified a clear relationship between chronic hepatic inflammation and HCC pathogenesis [3]. The inflammation associated with chronic hepatitis B virus (HBV) infection contributes to HCC [4]. Following HBV infection, Kupffer cells activate nuclear factor-kB
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