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

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Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression. / Kim, Seok Jun; Kang, Hyeok Gu; Kim, Kyungeun; Kim, Hoyoung; Zetterberg, Fredrik; Park, Young Soo; Cho, Hyun Soo; Hewitt, Stephen M.; Chung, Joon Yong; Nilsson, Ulf J.; Leffler, Hakon; Chun, Kyung Hee.

In: Gastric Cancer, 2021.

Research output: Contribution to journalArticle

Harvard

Kim, SJ, Kang, HG, Kim, K, Kim, H, Zetterberg, F, Park, YS, Cho, HS, Hewitt, SM, Chung, JY, Nilsson, UJ, Leffler, H & Chun, KH 2021, 'Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression', Gastric Cancer. https://doi.org/10.1007/s10120-021-01186-5

APA

Kim, S. J., Kang, H. G., Kim, K., Kim, H., Zetterberg, F., Park, Y. S., Cho, H. S., Hewitt, S. M., Chung, J. Y., Nilsson, U. J., Leffler, H., & Chun, K. H. (2021). Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression. Gastric Cancer. https://doi.org/10.1007/s10120-021-01186-5

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MLA

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Kim, Seok Jun ; Kang, Hyeok Gu ; Kim, Kyungeun ; Kim, Hoyoung ; Zetterberg, Fredrik ; Park, Young Soo ; Cho, Hyun Soo ; Hewitt, Stephen M. ; Chung, Joon Yong ; Nilsson, Ulf J. ; Leffler, Hakon ; Chun, Kyung Hee. / Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression. In: Gastric Cancer. 2021.

RIS

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

PY - 2021

Y1 - 2021

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.

KW - Galectin-3

KW - Gastric cancer

KW - GB1107

KW - STAT3

KW - WNT

U2 - 10.1007/s10120-021-01186-5

DO - 10.1007/s10120-021-01186-5

M3 - Article

C2 - 33834359

AN - SCOPUS:85104067681

JO - Gastric Cancer

JF - Gastric Cancer

SN - 1436-3291

ER -