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Insulin-Like Growth Factor 1 Receptor Drives Hepatocellular Carcinoma Growth and Invasion by Activating
Caiqun Bie1, Yanfang Chen2, Huijun Tang1
1Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, 518104, Guangdong, People's Republic of China.
Background:
Activation of the insulin-like growth factor 1 receptor (IGF-1R)-mediated Janus kinase (JAK)1/2-Stat3 pathway contributes to hepatocarcinogenesis. Specifically, a previous study showed that IGF-1R inhibition downregulated Midkine expression in hepatocellular carcinoma (HCC).
Aims:
The present study investigated the role of IGF-1R-JAK1/2-Stat3 and Midkine signaling in HCC, in addition to the molecular link between the IGF-1R-Stat3 pathway and Midkine.
Methods:
The expression levels of IGF-1R, Stat3, and Midkine were measured using reverse transcription-quantitative PCR, following which the association of IGF-1R with Stat3 and Midkine expression was evaluated in HCC. The molecular link between the IGF-1R-Stat3 pathway and Midkine was then investigated in vitro before the effect of IGF-1R-Stat3 and Midkine signaling on HCC growth and invasion was studied in vitro and in vivo.
Results:
IGF-1R, Stat3, and Midkine mRNA overexpressions were all found in HCC, where the levels of Stat3 and Midkine mRNA correlated positively with those of IGF-1R. In addition, Midkine mRNA level also correlated positively with Stat3 mRNA expression in HCC tissues. IGF-1R promoted Stat3 activation, which in turn led to the upregulation of Midkine expression in Huh7 cells. Similarly, Midkine also promoted Stat3 activation through potentiating JAK1/2 phosphorylation. Persistent activation of this Stat3-Midkine-Stat3 positive feedback signal loop promoted HCC growth and invasion, the inhibition of which resulted in significant antitumor activities both in vitro and in vivo.
Conclusions:
Constitutive activation of the IGF-1R-mediated Stat3-Midkine-Stat3 positive feedback loop is present in HCC, the inhibition of which can serve as a potential therapeutic intervention strategy for HCC.
Insights
Targeting the IGF-1R-Stat3-Midkine feedback loop shows promise for treating liver cancer. Inhibiting this pathway significantly reduced hepatocellular carcinoma growth and invasion in studies.
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- The insulin-like growth factor 1 receptor (IGF-1R) pathway, specifically involving Janus kinase (JAK)1/2 and Signal transducer and activator of transcription 3 (Stat3), is implicated in liver cancer development.
- Previous research indicated that inhibiting IGF-1R reduces Midkine expression in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate the roles of the IGF-1R-JAK1/2-Stat3 and Midkine signaling pathways in HCC.
- To elucidate the molecular connections between the IGF-1R-Stat3 pathway and Midkine in HCC.
Main Methods:
- Quantitative PCR was used to measure mRNA levels of IGF-1R, Stat3, and Midkine in HCC tissues.
- In vitro and in vivo experiments were conducted to assess the effects of signaling pathway modulation on HCC progression and invasion.
Main Results:
- Overexpression of IGF-1R, Stat3, and Midkine mRNA was observed in HCC, with positive correlations between IGF-1R and Stat3/Midkine levels, and between Stat3 and Midkine levels.
- IGF-1R activation led to Stat3 activation and subsequent Midkine upregulation in HCC cells.
- Midkine further promoted Stat3 activation via JAK1/2 phosphorylation, establishing a positive feedback loop that drives HCC growth and invasion.
- Inhibition of this Stat3-Midkine-Stat3 feedback loop demonstrated significant antitumor effects in vitro and in vivo.
Conclusions:
- A constitutive positive feedback loop involving IGF-1R, Stat3, and Midkine is active in HCC.
- Targeting and inhibiting this IGF-1R-Stat3-Midkine feedback loop represents a potential therapeutic strategy for HCC.
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