GAS5 represses endometrial cancer development via promoting anti‐tumor function of tumor‐associated macrophages

The tumor-suppressor role of Long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) have been proven in various types of cancer. However, the specific function of GAS5 in tumor-associated macrophages (TAMs) of endometrial cancer (EC) is elusive. qPCR results showed that GAS5 expression increased in EC tissues and primary TAMs from EC tumors. TAMs infiltration was significantly positively associated with the developmental stage of EC. Direct co-culture of GAS5-overexpressing TAMs and EC cells showed that GAS5 enhanced phagocytosis, antigen presentation, and activation of cytotoxic T cells, and repressed “Don’t eat me” signals between TAMs and EC cells. Tumor formation in immunodeficient mice showed that GAS5-overexpressing macrophages could repress EC formation in vivo. GAS5 promoted M1 polarization by activating the miR-21-PTEN-AKT signaling pathway and directly repressing the nuclear accumulation and phosphorylation of oncogenic yes-associated protein 1 (YAP1) in TAMs. GAS5 inhibited the development of EC from both innate and adaptive immunity by transforming TAMs from a pro-tumor to an anti-tumor phenotype. These anti-tumor effects of GAS5 on TAMs were mediated by the activation of the miR-21-PTEN-AKT pathway and inhibition of YAP1.