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ResearchIn-Press PreviewGastroenterologyOncology Open Access | 10.1172/JCI166224

CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages

Guohao Zhang,1 Zhaoxin Gao,1 Xiangyu Guo,1 Ranran Ma,1 Xiaojie Wang,1 Pan Zhou,1 Chunlan Li,1 Zhiyuan Tang,1 Ruinan Zhao,1 and Peng Gao2

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Zhang, G. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Gao, Z. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Guo, X. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Ma, R. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Wang, X. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Zhou, P. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Li, C. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Tang, Z. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Zhao, R. in: JCI | PubMed | Google Scholar

1Department of Pathology, Shandong University, Jinan, China

2Departemnt of Pathology, Shandong University, Jinan, China

Find articles by Gao, P. in: JCI | PubMed | Google Scholar

Published September 14, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI166224.
Copyright © 2023, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 14, 2023 - Version history
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Abstract

The metastasis of cancer cells is the main cause of death for patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5-7 domain of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ ERK signaling pathway, which resulted in interleukin-4 (IL4) and IL10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting transforming growth factor beta (TGFB1), which created a TGFB1/JUN/CAP2-positive feedback loop to activate CAP2 expression continuously. Furthermore, we identified Salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.

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