Journal
FRONTIERS IN ONCOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.727306
Keywords
gastric cancer; calmodulin 2; tumor-associated macrophages; angiogenesis; cancer
Categories
Funding
- National Natural Science Foundation of China [81602116]
- Hubei Provincial Natural Science Foundation [2016CFB195]
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The study revealed that CALM2 expression was elevated in GC tissues and cell lines, correlating with poor prognosis in GC patients. Both in vitro and in vivo experiments demonstrated that CALM2 could enhance tumor growth and lung metastasis, as well as promoting proliferation, migration, invasion, angiogenesis, and macrophage polarization. Mechanistically, CALM2 activated the JAK2/STAT3/HIF-1/VEGFA signaling pathway, facilitating GC metastasis and angiogenesis. Inhibition of JAK2 and HIF-1A attenuated the promoting effects of CALM2 on tumor cells, endothelial cells, and macrophages.
Background Tumor-associated macrophages (TAMs) are indispensable to mediating the connections between cells in the tumor microenvironment. In this study, we intended to research the function and mechanism of Calmodulin2 (CALM2) in gastric cancer (GC)-TAM microenvironment. Materials and methods CALM2 expression in GC tissues and GC cells was determined through quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). The correlation between CALM2 level and the survival rate of GC patients was assessed. The CALM2 overexpression or knockdown model was constructed to evaluate its role in GC cell proliferation, migration, and invasion. THP1 cells or HUVECs were co-cultured with the conditioned medium of GC cells. Tubule formation experiment was done to examine the angiogenesis of endothelial cells. The proliferation, migration, and polarization of THP1 cells were measured. A xenograft model was set up in BALB/c male nude mice to study CALM2x's effects on tumor growth and lung metastasis in vivo. Western Blot (WB) checked the profile of JAK2/STAT3/HIF-1/VEGFA in GC tissues and cells. Results In GC tissues and cell lines, CALM2 expression was elevated and positively relevant to the poor prognosis of GC patients. In in-vitro experiments, CALM2 overexpression or knockdown could facilitate or curb the proliferation, migration, invasion, and angiogenesis of HUVECs and M2 polarization of THP1 cells. In in-vivo experiments, CALM2 boosted tumor growth and lung metastasis. Mechanically, CALM2 could arouse the JAK2/STAT3/HIF-1/VEGFA signaling. It was also discovered that JAK2 and HIF-1A inhibition could attenuate the promoting effects of CALM2 on GC, HUVECs cells, and macrophages. Conclusion CALM2 modulates the JAK2/STAT3/HIF-1/VEGFA axis and bolsters macrophage polarization, thus facilitating GC metastasis and angiogenesis.
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