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 8

Salvianolic acid B is a putative molecular inhibitor of CAP2 and suppresses GC progression.

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Salvianolic acid B is a putative molecular inhibitor of CAP2 and suppres...
(A and B) IC50 determination of scutellarin (SCU) and salvianolic acid B (SAB) on MKN45 cells. After treatment of GC cells with a series of doses (1, 3.5, 11, 33, 100, and 300 μM) of inhibitors for 48 hours, cell viability was determined by CCK-8 assay. (C) Transwell migration assay of GC cells treated with SCU and SAB. Scale bars: 50 μm. (D) Protein expression of SRC/FAK/ERK/IL-4/IL-10 was determined by Western blotting after the GC cells were treated with SCU and SAB. (E and F) Mice subcutaneously injected with LV-NC MKN45 cells were treated with SCU and SAB, and then xenograft tumors were extracted (E) and weighed (F). (G) The growth curves of xenograft tumors were plotted based on the tumor size. The tumor size (V) was calculated based on the equation V = (length × width2)/2 (n = 5). (H) RNA expression of IL4 and IL10 in tumors was determined by quantitative PCR (n = 4). (I) Autodock predicts molecular docking of CAP2 with salvianolic acid B. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA with Tukey’s multiple-comparison test (C, F, and H), 2-way ANOVA test (G).