Abstract
BackgroundTumor-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 methodsCALM2 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.ResultsIn 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.ConclusionCALM2 modulates the JAK2/STAT3/HIF-1/VEGFA axis and bolsters macrophage polarization, thus facilitating GC metastasis and angiogenesis.
Highlights
Gastric cancer (GC) is the second leading cause of cancerconcerned mortality and the fourth most prevalent cancer across the world [1]
It was discovered that JAK2 and HIF-1A inhibition could attenuate the promoting effects of CALM2 on GC, Human umbilical vein endothelial cells (HUVECs) cells, and macrophages
As shown by the results, CALM2 expression was uplifted in GC tissues (Figure 1A). quantitative real-time PCR (qRT-PCR) ascertained its expression in GC tissues of patients in different clinical phases
Summary
Gastric cancer (GC) is the second leading cause of cancerconcerned mortality and the fourth most prevalent cancer across the world [1]. Tumor microenvironment (TME) refers to the internal environment where tumor cells form and live, covering tumor cells and fibroblasts, immune and inflammatory cells, glial cells, and other cells. Recent studies have disclosed that tumor-correlated macrophages (TAM) are the most common immune cells in TME. It is believed that these cells, polarized into M2-phenotype, enhance tumor development and pertain to poor tumor prognosis [4, 5]. Inhibited M2-phenotype macrophage polarization can hinder the malignant progression of cancers [6,7,8]. Tumor-associated macrophages (TAMs) are indispensable to mediating the connections between cells in the tumor microenvironment. We intended to research the function and mechanism of Calmodulin (CALM2) in gastric cancer (GC)TAM microenvironment
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