INHBA, transcriptionally activated by SPI1, facilitates gastric cancer progression by inducing macrophage recruitment and M2 polarization via activating the TGF-β signaling to increase CCL2.

Tumor-associated macrophages (TAMs) are associated with the occurrence, development, and poor prognosis of human cancers. Inhibin beta A subunit (INHBA) is found to be aberrantly upregulated in gastric cancer (GC). However, whether INHBA is involved in macrophage recruitment and M2 polarization is unclear. Herein, INHBA expression was increased in GC tumor tissues and cells. INHBA expression was positively correlated with macrophage infiltration and M2 macrophage markers. Knockdown of INHBA in GC cells suppressed macrophage recruitment and M2 polarization by downregulaitng CCL2 expression and secretion. Mechanistic assays showed that SPI1 could bind to INHBA and transcriptionally activate its expression. SPI1 promoted macrophage recruitment and M2 polarization by upregulating INHBA expression. Moreover, SPI1 induced CCL2 expression by regulating INHBA in GC cells. INHBA upregulated CCL2 expression by activating the TGF-β signaling. Furthermore, SPI1-induced macrophages facilitated cell proliferation, migration, and invasion by increasing INHBA expression. INHBA-induced macrophages promoted cell proliferation, migration, and invasion by inducing CCL2 expression. Additionally, knockdown of INHBA inhibited tumor growth in vivo. In conclusion, SPI1 induces the macrophage recruitment and M2 polarization by transcriptionally regulating INHBA to activating the TGF-β signaling, thereby upregulating CCL2 expression and then contributing to GC cell malignant progression. Targeting SPI1/INHBA/CCL2 axis might be a promising therapeutic strategy for GC and potentially used for cancer immunotherapy.