Open AccessGrowth arrest‐specific transcript 5 represses endometrial cancer development by promoting antitumor function of tumor‐associated macrophages
Author(s) -
Tu Jiajie,
Tan Xuewen,
Chen Yu,
Chen Yu,
Li Zhe,
Zhang Yuanyuan,
Chen Xiaochun,
Yang Huan,
Chen He,
Yu Zhiying
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15390
Subject(s) - pten , cancer research , tumor associated macrophage , protein kinase b , tensin , gas5 , biology , macrophage polarization , tumor microenvironment , pi3k/akt/mtor pathway , yap1 , downregulation and upregulation , signal transduction , long non coding rna , microbiology and biotechnology , macrophage , transcription factor , in vitro , gene , biochemistry , tumor cells
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.