Cancer-associated fibroblast-secreted IGFBP7 promotes gastric cancer by enhancing tumor associated macrophage infiltration via FGF2/FGFR1/PI3K/AKT axis

Abstract

We previously reported that IGFBP7 plays a role in maintaining mRNA stability of oncogenic lncRNA UBE2CP3 by RNA-RNA interaction in gastric cancer (GC). Clinical cohort studies had implied an oncogenic role of IGFBP7 in GC. However, the molecular mechanism of IGFBP7 in GC progression remains unknown. In this study, clinical analysis based on two independent cohorts showed that IGFBP7 was positively associated with poor prognosis and macrophage infiltration in GC. Loss-of-function studies confirmed the oncogenic properties of IGFBP7 in regulating GC cell proliferation and invasion. Mechanismly, IGFBP7 was highly expressed in cancer-associated fibroblasts (CAF) and mesenchymal cells, and was induced by epithelial-to-mesenchymal transition (EMT) signaling, since its expression was increased by TGF-beta treatment and reduced by overexpression of OVOL2 in GC. RNA sequencing, qRT-PCR, ELISA assay showed that IGFBP7 positively regulated FGF2 expression and secretion in GC. Transcriptome analysis revealed that FGFR1 was downregulated in M1 polarization but upregulated in M2 polarization. Exogenous recombinant IGFBP7 treatment in macrophages and GC cells further identified that IGFBP7 promotes tumor associated macrophage (TAM) polarization via FGF2/FGFR1/PI3K/AKT axis. Our finding here represented the first evidence that IGFBP7 promotes GC by enhancing TAM/M2 macrophage polarization through FGF2/FGFR1/PI3K/AKT axis.

Heterogeneity and plasticity of epithelial–mesenchymal transition (EMT) in cancer metastasis: Focusing on partial EMT and regulatory mechanisms

“…75 Moreover, EMT signalling can also promote tumour metastasis by regulating the expression of the oncogenic or tumour-suppressive long non-coding RNAs and proteins. 76,77 For instance, it has been reported that the EMT-induced lncRNA NR2F1-AS1 promoted gastric cancer metastasis via miR-29a/VAMP7 axis. 78 The interferon regulatory factor IRF6, which is repressed by EMT signalling, plays a tumour suppressive role in breast and gastric cancer.…”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…44 On the one hand, CAFs triggered phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway to induce the polarisation of M2 TAMs by secreting IGFBP7 and POSTN. 48,49 On the other hand, mixed TAMs of M1 and M2 enhanced the cancerpromoting roles of CAFs by increasing the secretion of IL-1β in TME, which accelerated the malignant progression of GC. 50 Moreover, MSCs derived from GC activated the JAK2/STAT3 pathway to enhance the polarisation of M2 TAMs by increasing the secretion of IL-6 and IL-8.…”

“…However, M2 TAMs inhibited the functions of T cells by increasing the accumulation of lipids in TME, thereby causing immune evasion of GC cells 44 . On the one hand, CAFs triggered phosphatidylinositol‐3‐kinase/protein kinase B (PI3K/Akt) pathway to induce the polarisation of M2 TAMs by secreting IGFBP7 and POSTN 48,49 . On the other hand, mixed TAMs of M1 and M2 enhanced the cancer‐promoting roles of CAFs by increasing the secretion of IL‐1β in TME, which accelerated the malignant progression of GC 50 .…”

“…USP14, a deubiquitinase, stabilises SIRT1 via deubiquitination, thereby activating PGC1‐α‐induced M2 polarisation in macrophages 45 . Several studies have reported that the activation of PI3K/AKT pathway in macrophages induced the M2 TAM polarisation 48,81–83 . Shu et al.…”

“…45 Several studies have reported that the activation of PI3K/AKT pathway in macrophages induced the M2 TAM polarisation. 48,[81][82][83] Shu et al revealed that the activation of GPR35 by ERR can enhance the ability of GC cells to induce the polarisation of M2 TAMs. 84 Similarly, MSR1 facilitated the polarisation of M2 TAMs by enhancing arginine and proline metabolism in macrophages.…”