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 Article has an altmetric score of 11

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 6

GC tissues with high expression of CAP2 are rich in M2 macrophages.

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GC tissues with high expression of CAP2 are rich in M2 macrophages. (A a...
(A and B) Effects of CAP2 overexpression on the mRNA levels of IL4 and IL10 were assessed using RT-PCR (n = 3). (C and D) Expression levels of IL-4 and IL-10 in the supernatant of GC cells were detected by ELISA (n = 3). (E) GC cell supernatants were concentrated using ultrafiltration tubes and subjected to Western blotting. (F) SRC inhibitor (PP2) and ERK inhibitor (SCH772984) were added to MKN45 cells, and the RNA levels of IL4 and IL10 were detected by RT-PCR (n = 4). (G) ERK inhibitor (SCH772984) was added to GC cells, and the protein levels of IL-4 and IL-10 were detected by Western blotting. (H) Protein expression of CD68, iNOS, and CD163 in GC paraffin-embedded specimens was determined using IHC. Scale bars: 200 μm; 100 μm (insets). (I) Relationship between CAP2 and macrophage cell infiltration was analyzed using the TIMER2.0 website. (J) Expression of CD163 in macrophages was detected by immunofluorescence. Green staining indicates CD163 expression. Scale bars: 25 μm. (K–N) Expression of CD206 in macrophages was detected using flow cytometry. (O and P) Expression of markers for M1 and M2 macrophages after coculture of GC cells and macrophages (n = 4). Data are presented as the mean ± SD. Two-tailed unpaired Student’s t test (A–D, O, and P), 1-way ANOVA with Tukey’s multiple-comparison test (F). *P < 0.05, **P < 0.01, ***P < 0.001.