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Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

OBJECTIVE: Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism...

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Autores principales: Wang, Zhu, Yang, Yang, Cui, Yancheng, Wang, Chao, Lai, Zhiyong, Li, Yansen, Zhang, Wei, Mustonen, Harri, Puolakkainen, Pauli, Ye, Yingjiang, Jiang, Kewei, Shen, Zhanlong, Wang, Shan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072013/
https://www.ncbi.nlm.nih.gov/pubmed/32194307
http://dx.doi.org/10.21147/j.issn.1000-9604.2020.01.09
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author Wang, Zhu
Yang, Yang
Cui, Yancheng
Wang, Chao
Lai, Zhiyong
Li, Yansen
Zhang, Wei
Mustonen, Harri
Puolakkainen, Pauli
Ye, Yingjiang
Jiang, Kewei
Shen, Zhanlong
Wang, Shan
author_facet Wang, Zhu
Yang, Yang
Cui, Yancheng
Wang, Chao
Lai, Zhiyong
Li, Yansen
Zhang, Wei
Mustonen, Harri
Puolakkainen, Pauli
Ye, Yingjiang
Jiang, Kewei
Shen, Zhanlong
Wang, Shan
author_sort Wang, Zhu
collection PubMed
description OBJECTIVE: Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified. METHODS: THP-1 monocytes were induced by PMA/interleukin (IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation (ChIP) assay were used to investigate the mechanism of transforming growth factor β2 (TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo. RESULTS: We found that Kindlin-2 expression was upregulated at both mRNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo. CONCLUSIONS: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.
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spelling pubmed-70720132020-03-19 Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis Wang, Zhu Yang, Yang Cui, Yancheng Wang, Chao Lai, Zhiyong Li, Yansen Zhang, Wei Mustonen, Harri Puolakkainen, Pauli Ye, Yingjiang Jiang, Kewei Shen, Zhanlong Wang, Shan Chin J Cancer Res Original Article OBJECTIVE: Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified. METHODS: THP-1 monocytes were induced by PMA/interleukin (IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation (ChIP) assay were used to investigate the mechanism of transforming growth factor β2 (TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo. RESULTS: We found that Kindlin-2 expression was upregulated at both mRNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo. CONCLUSIONS: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches. AME Publishing Company 2020-02 /pmc/articles/PMC7072013/ /pubmed/32194307 http://dx.doi.org/10.21147/j.issn.1000-9604.2020.01.09 Text en Copyright © 2020 Chinese Journal of Cancer Research. All rights reserved. http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Original Article
Wang, Zhu
Yang, Yang
Cui, Yancheng
Wang, Chao
Lai, Zhiyong
Li, Yansen
Zhang, Wei
Mustonen, Harri
Puolakkainen, Pauli
Ye, Yingjiang
Jiang, Kewei
Shen, Zhanlong
Wang, Shan
Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title_full Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title_fullStr Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title_full_unstemmed Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title_short Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis
title_sort tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through tgfβ2/nf-κb/kindlin-2 axis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072013/
https://www.ncbi.nlm.nih.gov/pubmed/32194307
http://dx.doi.org/10.21147/j.issn.1000-9604.2020.01.09
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