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
View: Text | PDF
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

×

Figure 2

JUN activates CAP2 transcription.

Options: View larger image (or click on image) Download as PowerPoint
JUN activates CAP2 transcription. (A) Schematic representation of trunca...
(A) Schematic representation of truncation of the CAP2 promoter region. (B) CAP2 core promoter region was detected in 293T cells by dual-luciferase activity assay (n = 4). (C and D) Dual-luciferase activity assay demonstrated that JUN promoted pGL-500 promoter activity in GC cells (n = 3). (E and F) RT-PCR assay indicated that JUN promoted the expression of CAP2 mRNA in GC cells (n = 4). (G) Western blot showed that JUN promoted the expression of CAP2 protein. (H and I) ChIP showed that JUN was significantly enriched in the CAP2 promoter region in GC tissues (n = 4). (J) Schematic representation of the luciferase reporter gene of the CAP2 promoter region and mutants (−386 to −369). (K) Dual-luciferase activity assays indicated that JUN binding mutants were unable to enhance pGL-500 promoter activity in MKN45 cells (n = 3). (L) mRNA expression of JUN and CAP2 was determined by RT-PCR (n = 26). Data are presented as the mean ± SD. One-way ANOVA with Tukey’s multiple-comparison test (B–D and K), 2-tailed unpaired Student’s t test (E, F, H, and I), Pearson’s correlation (L). *P < 0.05, **P < 0.01, ***P < 0.001.