Growth arrest-specific transcript 5 represses endometrial cancer development by promoting antitumor function of tumor-associated macrophages

作者：Tu, Jiajie^*; Tan, Xuewen; Chen, Yu; Li, Zhe; Zhang, Yuanyuan; Chen, Xiaochun; Yang, Huan; Chen, He; Yu, Zhiying^*

来源：Cancer Science, 2022, 113(8): 2496-2512.

DOI：10.1111/cas.15390

• cytotoxic T cell
• endometrial cancer
• GAS5
• phagocytosis
• TAM

The tumor-suppressor role of long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) has been proven in various types of cancer. However, the specific function of GAS5 in tumor-associated macrophages (TAMs) of endometrial cancer (EC) is elusive. Quantitative PCR results showed that GAS5 expression decreased in EC tissues and primary TAMs from EC tumors. Tumor-associated macrophage infiltration was significantly positively associated with the developmental stage of EC. Direct coculture 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 microRNA-21- phosphatase and tensin homolog (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 protumor to an antitumor phenotype. These antitumor effects of GAS5 on TAMs were mediated by the activation of the miR-21-PTEN-AKT pathway and inhibition of YAP1.

• 单位
  安徽医科大学; 南方医科大学; i; 1