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Crosstalk between W...
Crosstalk between WNT and STAT3 is mediated by galectin-3 in tumor progression
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- Kim, Seok Jun (author)
- Chosun University
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- Kang, Hyeok Gu (author)
- Yonsei University
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- Kim, Kyungeun (author)
- National Cancer Institute, USA,Sungkyunkwan University,Kangbuk Samsung Hospital
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- Kim, Hoyoung (author)
- Yonsei University
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- Zetterberg, Fredrik (author)
- Galecto Biotech AB, Sweden
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- Park, Young Soo (author)
- University of Ulsan
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- Cho, Hyun Soo (author)
- Yonsei University
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- Hewitt, Stephen M. (author)
- National Cancer Institute, USA
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- Chung, Joon Yong (author)
- National Cancer Institute, USA
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- Nilsson, Ulf J. (author)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Leffler, Hakon (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Chun, Kyung Hee (author)
- Yonsei University
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(creator_code:org_t)
- 2021-04-08
- 2021
- English.
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In: Gastric Cancer. - : Springer Science and Business Media LLC. - 1436-3291 .- 1436-3305. ; 24:5, s. 1050-1062
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Galectin-3
- Gastric cancer
- GB1107
- STAT3
- WNT
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Kim, Seok Jun
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Kang, Hyeok Gu
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Kim, Kyungeun
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Kim, Hoyoung
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Zetterberg, Fred ...
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Park, Young Soo
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show more...
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Cho, Hyun Soo
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Hewitt, Stephen ...
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Chung, Joon Yong
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Nilsson, Ulf J.
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Leffler, Hakon
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Chun, Kyung Hee
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Gastric Cancer
- By the university
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Lund University