Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression

Seok Jun Kim; Hyeok Gu Kang; Kyungeun Kim; Hoyoung Kim; Fredrik Zetterberg; Young Soo Park; Hyun Soo Cho; Stephen M. Hewitt; Joon Yong Chung; Ulf J. Nilsson; Hakon Leffler; Kyung Hee Chun

doi:10.1007/s10120-021-01186-5

Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression

Seok Jun Kim, Hyeok Gu Kang, Kyungeun Kim, Hoyoung Kim, Fredrik Zetterberg, Young Soo Park, Hyun Soo Cho, Stephen M. Hewitt, Joon Yong Chung, Ulf J. Nilsson, Hakon Leffler, Kyung Hee Chun

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Background: Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. Methods: We investigated how galectin-3 mediates the crosstalk between WNT/β-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice Results: Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of β-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and β-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. Conclusions: We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.

Original language	English
Pages (from-to)	1050-1062
Number of pages	13
Journal	Gastric Cancer
Volume	24
Issue number	5
DOIs	https://doi.org/10.1007/s10120-021-01186-5
Publication status	Published - 2021 Sept

Bibliographical note

Funding Information:
We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3−/−mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109).

Funding Information:
We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3 mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109). −/−

Publisher Copyright:
© 2021, The International Gastric Cancer Association and The Japanese Gastric Cancer Association.

All Science Journal Classification (ASJC) codes

Oncology
Gastroenterology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10120-021-01186-5

Cite this

@article{e37c3dc0f5564814ab889899df3b5bce,

title = "Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression",

abstract = "Background: Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. Methods: We investigated how galectin-3 mediates the crosstalk between WNT/β-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice Results: Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of β-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and β-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. Conclusions: We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.",

author = "Kim, {Seok Jun} and Kang, {Hyeok Gu} and Kyungeun Kim and Hoyoung Kim and Fredrik Zetterberg and Park, {Young Soo} and Cho, {Hyun Soo} and Hewitt, {Stephen M.} and Chung, {Joon Yong} and Nilsson, {Ulf J.} and Hakon Leffler and Chun, {Kyung Hee}",

note = "Funding Information: We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3−/−mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109). Funding Information: We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3 mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109). −/− Publisher Copyright: {\textcopyright} 2021, The International Gastric Cancer Association and The Japanese Gastric Cancer Association.",

year = "2021",

month = sep,

doi = "10.1007/s10120-021-01186-5",

language = "English",

volume = "24",

pages = "1050--1062",

journal = "Gastric Cancer",

issn = "1436-3291",

publisher = "Springer Japan",

number = "5",

}

TY - JOUR

T1 - Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression

AU - Kim, Seok Jun

AU - Kang, Hyeok Gu

AU - Kim, Kyungeun

AU - Kim, Hoyoung

AU - Zetterberg, Fredrik

AU - Park, Young Soo

AU - Cho, Hyun Soo

AU - Hewitt, Stephen M.

AU - Chung, Joon Yong

AU - Nilsson, Ulf J.

AU - Leffler, Hakon

AU - Chun, Kyung Hee

N1 - Funding Information: We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3−/−mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109). Funding Information: We thank Dr. M. Oshima (Kanazawa University, Japan) for providing K19-Wnt1/C2mE transgenic mice and Dr. F-T Liu (UC Davis, USA) for providing lgals3 mice. This work was supported by grants from National Research Foundation (NRF) of Korea funded by the Korean government (MSIP, No. NRF-2014R1A2A1A11050600, NRF-2016R1A5A1010764, NRF-2017R1C1B2005265, NRF-2017R1A2B2006238, NRF-2019R1A2C2089237, NRF-2020R1A4A1019063 and NRF-2020R1A2C110007811), the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIP, No. NRF-2015M3A9B6073835, NRF-2015M3A9B6073833), the Basic Science Research Program through the NRF of Korea funded by the Ministry of Education (No. NRF-2014R1A1A2055009), and the International Research & Development Program of the NRF funded by the Ministry of Education, Science and Technology (MEST) of Korea (No. NRF-2016K1A3A1A47921595), KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (21-BR-03-05) and the matching fund provided by Swedish Research Council (No. 2016-07109). −/− Publisher Copyright: © 2021, The International Gastric Cancer Association and The Japanese Gastric Cancer Association.

PY - 2021/9

Y1 - 2021/9

N2 - Background: Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. Methods: We investigated how galectin-3 mediates the crosstalk between WNT/β-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice Results: Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of β-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and β-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. Conclusions: We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.

AB - Background: Aberrant activation of the WNT/β-catenin and STAT3 signaling pathways plays a critical role in cancer progression. However, direct targeting of these pathways as an anti-cancer therapeutic approach needs to be reconsidered due to its serious side effects. Here, we demonstrate that overexpression of WNT induces STAT3 activation in a galectin-3-dependent manner. Methods: We investigated how galectin-3 mediates the crosstalk between WNT/β-catenin and STAT3 signaling and whether inhibition of galectin-3 can reduce gastric cancer. The molecular mechanisms were analyzed by biochemical assays using cultured gastric cancer cells, patient tissues, and genetically engineered mice. Moreover, we confirm of therapeutic effects of GB1107, a cell-penetrating galectin-3 specific inhibitor, using orthotopic gastric cancer-bearing mice Results: Increased levels of galectin-3 and STAT3 phosphorylation were detected in the stomach tissues of WNT1-overexpressing mouse models. Also, high expression levels and co-localization of β-catenin, pSTAT3, and galectin-3 in patients with advanced gastric cancer were correlated with a poorer prognosis. Galectin-3 depletion significantly decreased STAT3 Tyr705 phosphorylation, which regulates its nuclear localization and transcriptional activation. A peptide of galectin-3 (Y45-Q48) directly bound to the STAT3 SH2 domain and enhanced its phosphorylation. GB1107, a specific membrane-penetrating inhibitor of galectin-3, significantly reduced the activation of both STAT3 and β-catenin and inhibited tumor growth in orthotopic gastric cancer-bearing mice. Conclusions: We propose that galectin-3 mediates the crosstalk between the WNT and STAT3 signaling pathways. Therefore GB1107, a galectin-3-specific inhibitor, maybe a potent agent with anti-gastric cancer activity. Further studies are needed for its clinical application in gastric cancer therapy.

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U2 - 10.1007/s10120-021-01186-5

DO - 10.1007/s10120-021-01186-5

M3 - Article

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AN - SCOPUS:85104067681

SN - 1436-3291

VL - 24

SP - 1050

EP - 1062

JO - Gastric Cancer

JF - Gastric Cancer

IS - 5

ER -

Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression

Abstract

Bibliographical note

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