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Growth arrest-specific transcript 5 represses endometrial cancer development by promoting antitumor function of
Jiajie Tu1,2, Xuewen Tan2, Yu Chen1
1Department of Gynecology, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China.
Abstract:
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.
Insights
Long noncoding RNA GAS5 suppresses endometrial cancer by reprogramming tumor-associated macrophages. GAS5 enhances macrophage anti-tumor activity, inhibiting cancer growth through immune modulation.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Long noncoding RNA (lncRNA) GAS5 is a known tumor suppressor.
- The role of GAS5 in endometrial cancer (EC) and tumor-associated macrophages (TAMs) is unclear.
Purpose of the Study:
- To investigate the function of GAS5 in TAMs within the context of endometrial cancer.
- To elucidate the molecular mechanisms by which GAS5 influences TAM phenotype and anti-tumor activity.
Main Methods:
- Quantitative PCR to assess GAS5 expression in EC tissues and TAMs.
- Co-culture experiments of GAS5-overexpressing TAMs and EC cells.
- In vivo tumor formation studies in immunodeficient mice.
- Analysis of immune cell activation, phagocytosis, and signaling pathways (miR-21-PTEN-AKT, YAP1).
Main Results:
- GAS5 expression was reduced in EC tissues and TAMs.
- GAS5 overexpression in TAMs enhanced phagocytosis, antigen presentation, and T cell activation while reducing "Don't eat me" signals.
- GAS5-overexpressing macrophages inhibited EC formation in vivo.
- GAS5 promoted M1 TAM polarization by activating the miR-21-PTEN-AKT pathway and inhibiting YAP1.
Conclusions:
- GAS5 acts as a tumor suppressor in endometrial cancer by modulating TAMs.
- GAS5 transforms TAMs from a protumor to an antitumor phenotype, enhancing innate and adaptive immunity against EC.
- The miR-21-PTEN-AKT pathway and YAP1 are key mediators of GAS5's anti-tumor effects in TAMs.
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