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Insulin-Like Growth Factor 1 Receptor Drives Hepatocellular Carcinoma Growth and Invasion by Activating Stat3-Midkine-Stat3 Loop

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Abstract

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.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

HCC:

Hepatocellular carcinoma

IGF-1:

Insulin-like growth factor 1

IGF-1R:

Insulin-like growth factor 1 receptor

JAK1/2:

Janus kinase ½

MAPK:

Mitogen-activated protein kinase

MANT:

Matched adjacent nontumorous tissues

MTT:

Methyl thiazolyl tetrazolium

NALT:

Normal adult liver tissues

PI3K:

Phosphatidyl-inositol-3 kinase

qChIP:

Quantitative chromatin immunoprecipitation

PIAS:

Protein inhibitors of activated Stats

RNAi:

RNA interference

SHP:

SH2-containing phosphatases

shRNA:

Short hairpin RNA

siRNAs:

Small interfering RNAs

SOCS:

Suppressors of cytokine signaling

Stat3:

Signal transducer and activator of transcription 3

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Acknowledgments

The authors appreciate the patients, study investigators, and staff who participated in this study.

Funding

This study was supported by Grants from Shenzhen Science and Technology Project of China (No. JCYJ20160428100513152); Science and Technology Funding Project of Hunan Province, China (No. 2017SK4010); 7th batch Key Laboratory Project of Colleges and Universities of Hunan Province (2019–301); Medical Science and Technology Research Fund of Guangdong Province (No. A2019256); Natural Science Foundation of Guangdong Province (No. 2018A0303130302); and Medical Science and Technology Foundation of Guangdong Province (No. A2018011).

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Author notes

  1. Caiqun Bie, Yanfang Chen, Huijun Tang, and Qing Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Shenzhen Shajing Hospital, Guangzhou Medical University, Shenzhen, 518104, Guangdong, People’s Republic of China

    Caiqun Bie, Huijun Tang & Shenglan Wu

  2. Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Yanfang Chen, Lu Zhong, Ying Shi, Junqin Lin, Junlong Lai & Shaohui Tang

  3. Department of Interventional Vascular Surgery, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, Hunan, People’s Republic of China

    Qing Li

  4. Department of Endocrinology, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, Hunan, People’s Republic of China

    Xiaojuan Peng

Authors
  1. Caiqun Bie
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Contributions

S.H.T. designed the study. C.Q.B., Y.F.C., H.J.T., Q.L., L.Z., X.J.P., S.Y., J.Q.L., J.L.L., and S.L.W. performed the experiments. C.Q.B., Y.F.C., H.J.T., and Q.L. conducted statistical analysis. C.Q.B., Y.F.C., and S.H.T. wrote the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Shaohui Tang.

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The authors declare that they have no conflict of interests.

Ethics approval and consent to participate

The study was approved by the medical ethics committee of the First Affiliated Hospital of Jinan University, China. Written consent was obtained from all participants. This study conforms to the Declaration of Helsinki.

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Written informed consent for publication was obtained from the patients. All authors have agreed to publish this manuscript.

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Bie, C., Chen, Y., Tang, H. et al. Insulin-Like Growth Factor 1 Receptor Drives Hepatocellular Carcinoma Growth and Invasion by Activating Stat3-Midkine-Stat3 Loop. Dig Dis Sci 67, 569–584 (2022). https://doi.org/10.1007/s10620-021-06862-1

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