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Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells

Oncogene volume 38, pages 5805–5816 (2019)Cite this article

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A Correction to this article was published on 11 December 2023

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Abstract

Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32), is frequently overexpressed in early stages of gastric cancers. We utilized in vitro assays, 3D gastric gland organoid cultures, mouse models, and human tissue samples to investigate the biological and molecular impact of DARPP-32 on activation of IGF1R and STAT3 signaling and gastric tumorigenesis. DARPP-32 enhanced phosphorylation of IGF1R (Y1135), a step that was critical for STAT3 phosphorylation at Y705, nuclear localization, and transcription activation. By using proximity ligation and co-immunoprecipitation assays, we found that IGF1R and DARPP-32 co-existed in the same protein complex. Binding of DARPP-32 to IGF1R promoted IGF1R phosphorylation with subsequent activation of downstream SRC and STAT3. Analysis of gastric tissues from the TFF1 knockout (KO) mouse model of gastric neoplasia, demonstrated phosphorylation of STAT3 in the early stages of gastric tumorigenesis. By crossing the TFF1 KO mice with DARPP-32 (DP) knockout (KO) mice, that have normal stomach, we obtained double knockout (TFF1 KO/DP KO). The gastric mucosa from the double KO mice did not show phosphorylation of IGF1R or STAT3. In addition, the TFF1 KO/DP KO mice had a significant delay in developing neoplastic gastric lesions. Analysis of human gastric cancer tissue microarrays, showed high levels of DARPP-32 and positive immunostaining for nuclear STAT3 in cancer tissues, as compared to non-cancer histologically normal tissues. In summary, the DARPP-32–IGF1R signaling axis plays a key role in regulating the STAT3 signaling, a critical step in gastric tumorigenesis.

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Acknowledgements

This study was supported by the U.S. National Institutes of Health (R01CA93999), Research Career Scientist award (1IK6BX003787), and a merit award (I01BX001179) from the U.S. Department of Veterans affairs (W. El-Rifai). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, National Institutes of Health, or the University of Miami.

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Authors and Affiliations

  1. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Shoumin Zhu, Mohammed Soutto, Zheng Chen, Alexander Zaika, Dunfa Peng & Wael El-Rifai

  2. Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA

    Mohammed Soutto, Zheng Chen, Alexander Zaika & Wael El-Rifai

  3. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Alexander Zaika, Dunfa Peng & Wael El-Rifai

  4. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    M. Blanca Piazuelo

  5. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    M. Kay Washington

  6. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

    Abbes Belkhiri

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  1. Shoumin Zhu
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Correspondence to Wael El-Rifai.

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Zhu, S., Soutto, M., Chen, Z. et al. Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells. Oncogene 38, 5805–5816 (2019). https://doi.org/10.1038/s41388-019-0843-1

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