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FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer

BACKGROUND: FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown. METHODS: In vitro and in vivo ass...

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Autores principales: Peng, SanFei, Yin, YuHan, Zhang, YiZheng, Zhu, Feng, Yang, Ge, Fu, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071617/
https://www.ncbi.nlm.nih.gov/pubmed/37016377
http://dx.doi.org/10.1186/s13046-023-02652-x
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author Peng, SanFei
Yin, YuHan
Zhang, YiZheng
Zhu, Feng
Yang, Ge
Fu, Yang
author_facet Peng, SanFei
Yin, YuHan
Zhang, YiZheng
Zhu, Feng
Yang, Ge
Fu, Yang
author_sort Peng, SanFei
collection PubMed
description BACKGROUND: FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown. METHODS: In vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting, (32)p-labeled isotope radioautography assays, vitro kinase assays, and TOPK knockout mice. RESULTS: FYN was found to be significantly upregulated in GC tissues as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice. CONCLUSIONS: FYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02652-x.
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spelling pubmed-100716172023-04-05 FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer Peng, SanFei Yin, YuHan Zhang, YiZheng Zhu, Feng Yang, Ge Fu, Yang J Exp Clin Cancer Res Research BACKGROUND: FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown. METHODS: In vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting, (32)p-labeled isotope radioautography assays, vitro kinase assays, and TOPK knockout mice. RESULTS: FYN was found to be significantly upregulated in GC tissues as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice. CONCLUSIONS: FYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02652-x. BioMed Central 2023-04-04 /pmc/articles/PMC10071617/ /pubmed/37016377 http://dx.doi.org/10.1186/s13046-023-02652-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Peng, SanFei
Yin, YuHan
Zhang, YiZheng
Zhu, Feng
Yang, Ge
Fu, Yang
FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title_full FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title_fullStr FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title_full_unstemmed FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title_short FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
title_sort fyn/topk/hspb1 axis facilitates the proliferation and metastasis of gastric cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071617/
https://www.ncbi.nlm.nih.gov/pubmed/37016377
http://dx.doi.org/10.1186/s13046-023-02652-x
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