CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages
Guohao Zhang, Zhaoxin Gao, Xiangyu Guo, Ranran Ma, Xiaojie Wang, Pan Zhou, Chunlan Li, Zhiyuan Tang, Ruinan Zhao, Peng Gao
Guohao Zhang, Zhaoxin Gao, Xiangyu Guo, Ranran Ma, Xiaojie Wang, Pan Zhou, Chunlan Li, Zhiyuan Tang, Ruinan Zhao, Peng Gao
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Research Article Gastroenterology Oncology

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

Abstract

The metastasis of cancer cells is the main cause of death in 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 to WD7 domains 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 IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting 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.

Authors

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

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Figure 1

CAP2 is upregulated in human GC tissues and is associated with a poor prognosis.

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CAP2 is upregulated in human GC tissues and is associated with a poor pr...
(A) CAP2 mRNA expression in GC tissues and nontumorous gastric tissues was detected with reverse transcriptase PCR (RT-PCR) (n[GC] = 50, n[Nontumorous] = 31). (B) CAP2 mRNA expression in GC tissues with and without LNM was detected by qPCR (n[positive] = 31, n[negative] = 19). The violin plot shows the mean and interquartile range, and the width shows the probability density. (C–F) Expression of CAP2 protein in GC paraffin-embedded tissue was detected by IHC. Representative images of CAP2 expression in normal gastric mucosa and GC tissues of different grades. Original magnification, ×100; scale bars: 100 μm. (G) Percentage of the high and low CAP2 expression levels in GC samples with different metastatic status and in normal gastric mucosal samples. (H and I) Kaplan-Meier curves of overall survival and disease-free survival for CAP2 expression. The cutoff value was obtained using the median analysis. (The numbers of patients with high and low CAP2 expression were equal. n[low] = 61, n[high] = 61.) Two-tailed unpaired Student’s t test (A and B), χ2 test (G), log-rank test (H and I). *P < 0.05, ***P < 0.001.