Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression

Te Sheng Chang, Yu Chih Wu, Ching Chi Chi, Wei Chi Su, Pey Jium Chang, Kam Fai Lee, Tao Hsin Tung, Jui Wang, Jun-Jen Liu, Shui Yi Tung, Liang Mou Kuo, Hong Nerng Ho, Thai Y. Ling, Yen-Hua Huang

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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.

Original languageEnglish
Pages (from-to)201-210
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

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IGF Type 1 Receptor
Hepatitis B virus
Hepatocellular Carcinoma
Interleukin-6
RNA Interference
Recurrence
Neoplasms
Growth Factor Receptors
Kaplan-Meier Estimate
Survival Analysis
Luciferases
Serum
Heterografts
Real-Time Polymerase Chain Reaction
Intercellular Signaling Peptides and Proteins
Research Design
Transcription Factors
Animal Models
Western Blotting
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression. / Chang, Te Sheng; Wu, Yu Chih; Chi, Ching Chi; Su, Wei Chi; Chang, Pey Jium; Lee, Kam Fai; Tung, Tao Hsin; Wang, Jui; Liu, Jun-Jen; Tung, Shui Yi; Kuo, Liang Mou; Ho, Hong Nerng; Ling, Thai Y.; Huang, Yen-Hua.

In: Clinical Cancer Research, Vol. 21, No. 1, 01.01.2015, p. 201-210.

Research output: Contribution to journalArticle

Chang, Te Sheng ; Wu, Yu Chih ; Chi, Ching Chi ; Su, Wei Chi ; Chang, Pey Jium ; Lee, Kam Fai ; Tung, Tao Hsin ; Wang, Jui ; Liu, Jun-Jen ; Tung, Shui Yi ; Kuo, Liang Mou ; Ho, Hong Nerng ; Ling, Thai Y. ; Huang, Yen-Hua. / Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 1. pp. 201-210.
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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.",
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T1 - Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression

AU - Chang, Te Sheng

AU - Wu, Yu Chih

AU - Chi, Ching Chi

AU - Su, Wei Chi

AU - Chang, Pey Jium

AU - Lee, Kam Fai

AU - Tung, Tao Hsin

AU - Wang, Jui

AU - Liu, Jun-Jen

AU - Tung, Shui Yi

AU - Kuo, Liang Mou

AU - Ho, Hong Nerng

AU - Ling, Thai Y.

AU - Huang, Yen-Hua

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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