CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages
Guohao Zhang, … , Ruinan Zhao, Peng Gao
Guohao Zhang, … , Ruinan Zhao, Peng Gao
Published September 14, 2023
Citation Information: J Clin Invest. 2023;133(21):e166224. https://doi.org/10.1172/JCI166224.
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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 3

CAP2 promotes GC progression.

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CAP2 promotes GC progression. (A and B) The migration and invasion abili...
(A and B) The migration and invasion ability of MKN45 cells was determined by Transwell assay. Original magnification, ×40; scale bar: 200 μm (n = 4). (C) GC cells were injected into the tail vein of mice to obtain lung xenografts. After LV-NC (n = 5) and LV-shCAP2 (n = 6) were injected into the tail vein of mice, the siCAP2 group (n = 5) was treated with siRNA every 3 days. (D and E) Number of lung transplanted tumors (D) and the ratio of transplanted tumor/normal lung tissue area (E) in nude mice. (F) Representative photographs of lung metastases on day 36. Scale bars: 1 mm; 500 μm (insets). (G) H&E staining showed that the LV-shCAP2 group had an intact capsule, while the LV-shNC group had local infiltration. Scale bars: 1 mm; 500 μm (insets). (H and I) LV-shCAP2 or negative control was used for mouse subcutaneous tumorigenesis experiments. At 36 days after the subcutaneous injection, tumor weight was measured (H). Tumor volumes were measured weekly, and tumor growth curves were drawn (I). Data are presented as the mean ± SD. Two-tailed unpaired Student’s t test (A, B, and H), 1-way ANOVA with Tukey’s multiple-comparison test (D and E), 2-way ANOVA test (I). *P < 0.05, **P < 0.01, ***P < 0.001.