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A synergistic partnership between IL-33/ST2 and Wnt pathway through Bcl-xL drives gastric cancer stemness and metastasis

Oncogene volume 42, pages 501–515 (2023)Cite this article

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Abstract

ST2 functions as a receptor for the cytokine IL-33. It has been implicated in carcinogenesis. In this study, we sought to mechanistically determine how ST2 and IL-33 function to support cancer stem cell (CSC) activity and drive gastric cancer (GC) pathogenesis. ST2+ subpopulation spontaneously arose during gastric tumorigenesis. A thorough evaluation of ST2 and IL-33 expression in gastric tumors revealed that they show an overlapping expression pattern, notably in poor differentiated GC and metastasis foci. Moreover, their expression levels are clinically correlated to cancer progression. Using a genetic model of CSC-driven gastric carcinogenesis, ST2+ subpopulation displays increased tumorigenicity, chemoresistance and metastatic potentials through increased survival fitness endowed by an elevated MAPK-regulated Bcl-xL. The IL-33/ST2 axis enhances the self-renewal and survival of GC stem cells and organoids. Importantly, we observed a synergistic cooperation between IL-33/ST2 and the canonical Wnt pathway in transactivating Wnt-dependent transcription and supporting CSC activity, a partnership that was abrogated by inhibiting Bcl-xL. Concordant with this, ST2+ subpopulation was targeted by MEK1/2 and Bcl-xL-specific inhibitors. These findings establish ST2 as a functional CSC marker that fortifies the Wnt signal while availing a novel therapeutic strategy to suppress GC progression by targeting the IL-33/ST2/Bcl-xL signaling axis.

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Fig. 1: Investigation of IL-33 and ST2 expression patterns in gastric cancer.
Fig. 2: Analysis of ST2 and IL-33 expression patterns in S1M orthotopic model.
Fig. 3: ST2 and IL-33 expression in human GC and its clinical significance.
Fig. 4: IL-33/ST2 axis in GC stemness.
Fig. 5: Resistance to chemotherapy and anoikis in ST2+ subpopulation.
Fig. 6: IL-33/ST2 axis induces Bcl-xL via MAPK pathway activation.
Fig. 7: Effect of ST2 on tumor formation, growth, and metastasis in in vivo transplantation models.
Fig. 8: IL-33/ST2 axis synergizes WNT signaling to enhance GC stemness depending on MAPK-Bcl-xL pathway.

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Data availability

The public datasets used in this study listed in the appropriate Supplementary information section are available on Gene Expression Omnibus (GEO) database. All the other data are available from the corresponding author on reasonable request.

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Funding

This research was supported by grants from the National Research Foundation (NRF) funded by the Korean government (2016M3A9D5A01952416, 2020R1C1C1014059, 2021M3H9A1030260). This study was also supported by 2021 Research Grant from Kangwon National University.

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Authors and Affiliations

  1. Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do, 24341, South Korea

    Jong-Wan Kwon, Sang-Hyuk Seok, Hyeok-Won An & Jun Won Park

  2. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, South Korea

    Somi Kim & Jong Kyoung Kim

  3. Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan

    Anahita Dev Choudhury & Dominic C. Voon

  4. Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Japan

    Anahita Dev Choudhury & Dominic C. Voon

  5. Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea

    Sang-Ho Woo, Jeong-Seop Oh & Dae-Yong Kim

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  1. Jong-Wan Kwon
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Contributions

J-WK—data curation: lead; formal analysis: lead; investigation: lead; methodology: lead; writing – original draft: equal. S-HS—investigation: supporting; methodology: supporting; resources: supporting. SK—investigation: supporting; methodology: supporting; resources: supporting. H-W—investigation: supporting; methodology: supporting. ADC—writing – review and editing: supporting. S-HW—resources: supporting. J-SO—resources: supporting. JKK—data curation: supporting; supervision: supporting. DCV—data curation: supporting; supervision: lead; writing – review and editing: lead. D-YK—funding acquisition: supporting; project administration: lead; resources: supporting; supervision: equal; writing – review and editing: supporting. JWP—conceptualization: lead; data curation: lead; formal analysis: lead; funding acquisition: lead; investigation: lead; project administration: lead; supervision: lead; writing – original draft: lead; writing – review and editing: lead.

Corresponding authors

Correspondence to Dominic C. Voon, Dae-Yong Kim or Jun Won Park.

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Kwon, JW., Seok, SH., Kim, S. et al. A synergistic partnership between IL-33/ST2 and Wnt pathway through Bcl-xL drives gastric cancer stemness and metastasis. Oncogene 42, 501–515 (2023). https://doi.org/10.1038/s41388-022-02575-5

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