FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
Abstract 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 v...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-04-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02652-x |
| _version_ | 1797849852940386304 |
|---|---|
| author | SanFei Peng YuHan Yin YiZheng Zhang Feng Zhu Ge Yang Yang Fu |
| author_facet | SanFei Peng YuHan Yin YiZheng Zhang Feng Zhu Ge Yang Yang Fu |
| author_sort | SanFei Peng |
| collection | DOAJ |
| description | Abstract 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, 32p-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. |
| first_indexed | 2024-04-09T18:50:54Z |
| format | Article |
| id | doaj.art-ae9b73fac6164b2186d7a142d62cf1f5 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-09T18:50:54Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-ae9b73fac6164b2186d7a142d62cf1f52023-04-09T11:29:53ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-04-0142112010.1186/s13046-023-02652-xFYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancerSanFei Peng0YuHan Yin1YiZheng Zhang2Feng Zhu3Ge Yang4Yang Fu5Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou, UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou, UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou, UniversityCancer Research Institute, The Affiliated Hospital of Guilin Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou, UniversityAbstract 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, 32p-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.https://doi.org/10.1186/s13046-023-02652-xFYNTOPKGastric Cancer ProgressionPhosphorylationHSPB1 |
| spellingShingle | SanFei Peng YuHan Yin YiZheng Zhang Feng Zhu Ge Yang Yang Fu FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer Journal of Experimental & Clinical Cancer Research FYN TOPK Gastric Cancer Progression Phosphorylation HSPB1 |
| 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 | FYN TOPK Gastric Cancer Progression Phosphorylation HSPB1 |
| url | https://doi.org/10.1186/s13046-023-02652-x |
| work_keys_str_mv | AT sanfeipeng fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer AT yuhanyin fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer AT yizhengzhang fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer AT fengzhu fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer AT geyang fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer AT yangfu fyntopkhspb1axisfacilitatestheproliferationandmetastasisofgastriccancer |