Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression
Journal
Clinical Cancer Research
Journal Volume
21
Journal Issue
1
Pages
201-210
Date Issued
2015
Author(s)
Chang T.-S
Wu Y.-C
Chi C.-C
Su W.-C
Chang P.-J
Lee K.-F
Tung T.-H
Liu J.-J
Tung S.-Y
Kuo L.-M
Huang Y.-H.
Abstract
Purpose: To unravel the role of interleukin (IL)-6 and insulinlike growth factor (IGF)-I receptor (IGFIR) in expressing stemnessrelated properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC). Experimental Design: 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. Results: 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 confi ned 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. Conclusions: 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. ? 2014 AACR.
SDGs
Other Subjects
interleukin 6; luciferase; messenger RNA; octamer transcription factor 4; somatomedin C receptor; STAT3 protein; transcription factor NANOG; homeodomain protein; interleukin 6; NANOG protein, human; octamer transcription factor 4; POU5F1 protein, human; somatomedin receptor; adult; aged; animal experiment; animal model; animal tissue; Article; autocrine effect; cancer prognosis; cancer recurrence; cancer survival; controlled study; enzyme linked immunosorbent assay; female; hepatitis B; human; human cell; human tissue; immunohistochemistry; in vitro study; in vivo study; liver cell carcinoma; major clinical study; male; nonhuman; protein blood level; protein determination; protein expression; protein induction; protein localization; protein phosphorylation; protein targeting; real time polymerase chain reaction; reverse transcription polymerase chain reaction; RNA interference; signal transduction; tumor xenograft; upregulation; Western blotting; animal; biosynthesis; blood; drug screening; gene expression regulation; genetics; Hepatitis B virus; Kaplan Meier method; liver cell carcinoma; liver tumor; mouse; Neoplasm Recurrence, Local; pathogenicity; pathology; prognosis; tumor cell line; virology; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Hepatitis B virus; Homeodomain Proteins; Humans; Interleukin-6; Kaplan-Meier Estimate; Liver Neoplasms; Mice; Neoplasm Recurrence, Local; Octamer Transcription Factor-3; Prognosis; Receptors, Somatomedin; Xenograft Model Antitumor Assays
Type
journal article