Cytoplasmic expression of G protein-coupled estrogen receptor 1 correlates with poor postoperative prognosis in non-small cell lung cancer

Li, Zhenhua; Liu, Chang; Liu, Qinghua; Wang, Jian; Wang, Ying; Wang, Yanfei; Deng, Shou-Jun; Li, Dingbiao

doi:10.21037/jtd-22-29

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…Wang et al screened for G protein-coupled receptor-related genes through immune infiltrationrelated genes [60]; Liu et al studied the effects of G protein-coupled receptor antagonists on lung adenocarcinoma [61]; Jala VR, Li ZH, Wu G and Yao S et al studied single gene of G protein coupled receptor [62][63][64][65]; Touge H et al study was the effect of G protein coupled receptor on the morphology of lung adenocarcinoma cells [66]; Khan M's review type of study mainly talked about the relevance of GPCR in the treatment of lung adenocarcinoma [67]; Gao Y and Fujimoto J was mainly experimental and did not use bioinformatics on a large scale [68,69].Our study is G protein-coupled receptor fully characterised and some of the genes have not been studied yet.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics identification of GPCR gene features in lung adenocarcinoma based on multiple machine learning combinations

Xie,

Pan,

Wang

et al. 2024

J. Cancer

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Background: Lung adenocarcinoma is a common malignant tumor that ranks second in the world and has a high mortality rate. G protein-coupled receptors (GPCRs) have been reported to play an important role in cancer; however, G protein-coupled receptor-associated features have not been adequately investigated. Methods: In this study, GPCR-related genes were screened at single-cell and bulk transcriptome levels based on AUcell, single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network (WGCNA) analysis. And a new machine learning framework containing 10 machine learning algorithms and their multiple combinations was used to construct a consensus G protein-coupled receptor-related signature (GPCRRS). GPCRRS was validated in the training set and external validation set. We constructed GPCRRS-integrated nomogram clinical prognosis prediction tools. Multi-omics analyses included genomics, single-cell transcriptomics, and bulk transcriptomics to gain a more comprehensive understanding of prognostic features. We assessed the response of risk subgroups to immunotherapy and screened for personalized drugs targeting specific risk subgroups. Finally, the expression of key GPCRRS genes was verified by RT-qPCR. Results: In this study, we identified 10 GPCR-associated genes that were significantly associated with the prognosis of lung adenocarcinoma by single-cell transcriptome and bulk transcriptome. Univariate and multivariate showed that the survival rate was higher in low risk than in high risk, which also suggested that the model was an independent prognostic factor for LUAD. In addition, we observed significant differences in biological function, mutational landscape, and immune cell infiltration in the tumor microenvironment between high and low risk groups. Notably, immunotherapy was also relevant in the high and low risk groups. In addition, potential drugs targeting specific risk subgroups were identified. Conclusion: In this study, we constructed and validated a lung adenocarcinoma G protein-coupled receptor-related signature, which has an important role in predicting the prognosis of lung adenocarcinoma and the effect of immunotherapy. It is hypothesized that LDHA, GPX3 and DOCK4 are new potential targets for lung adenocarcinoma, which can achieve breakthroughs in prognosis prediction, targeted prevention and treatment of lung adenocarcinoma and provide important guidance for anti-tumor.

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Section: Discussionmentioning

confidence: 99%

Multi-omics identification of GPCR gene features in lung adenocarcinoma based on multiple machine learning combinations

Xie,

Pan,

Wang

et al. 2024

J. Cancer

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“…(or G-15 treatment) increased cisplatin sensitivity [32] AGS and MGC-803 cell lines N.D. Co-expression of cytoplasmic and nuclear GPER expression was associated with a poor prognosis. Nuclear GPER is correlated with ER-β [132] Tissue samples from LC tumors and adjacent normal tissues A549, H23, H1299, H1792, H1395, H1435, H1793, H1944, H2073 (LC), and HPL1D, HBEC2-E, HBEC2-KT, and HBEC3-KT (epithelial lung) cell lines N.D.…”

Section: Gper Induces Cisplatin Resistance By Promoting Emt Gper Acti...mentioning

confidence: 99%

“…Regarding the subcellular localization of GPER, in non-small cell lung cancer (NSCLC) samples (including lung adenocarcinoma and squamous cell carcinoma), it was expressed in both the cytoplasm and nucleus [131,132]. A correlation was found in the expression of GPER and ER-β [131,132]. Moreover, higher cytoplasmic expression of GPER was associated with higher tumor stages with less cell differentiation [131].…”

Section: Lung Cancermentioning

confidence: 99%

The G Protein-Coupled Estrogen Receptor GPER in the Development and Progression of Cancer

Torres-López,

Olivas-Aguirre,

Dobrovinskaya

2024

Receptors

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The high incidence of cancer and the prevalence of chemoresistance are serious problems worldwide, underscoring the urgency of novel research focused on understanding the underlying mechanisms and finding new therapeutic targets. Recently, the G protein-coupled estrogen receptor (GPER) has received increasing attention, and it has been studied in various models, including physiological and pathological conditions, using appropriate pharmacological and molecular biological strategies. Numerous studies indicate that GPER plays an important role in cancer progression and resistance. This review focuses on the structure of GPER, the diversity of its ligands and GPER-activated signaling pathways, the role of GPER in cancer progression, and mechanisms of chemoresistance, with special emphasis on different cancer types and the tumor microenvironment. GPER was evidenced to exhibit conformational plasticity and different ligand binding modes. Therefore, GPER-mediated effects can be triggered by estrogens or various estrogen mimetics, including synthesized compounds, licensed drugs, or exogenous environmental compounds. We found multiple reports evidencing that GPER is differentially expressed in healthy tissues and tumors and plays a protumor role in breast, ovarian, lung, thyroid, and endometrial cancers. Additionally, there are several studies that indicate that GPER expression in cells of the tumor microenvironment may also contribute to cancer progression. Among the major mechanisms of GPER-mediated chemoresistance are the epithelial-mesenchymal transition, the overexpression of multidrug resistance pumps, and autophagy regulation.

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“…The GPER1 protein is known to be biologically active and highly expressed in a range of solid tumors, particularly those with sex-based differences in their incidence rates, such as breast, endometrial, thyroid, and colon cancer (Hernandez-Silva et al 2020;Hsu et al 2019;Jacenik et al 2019;Xu et al 2019). Recently, research revealed that GPER1 expression was elevated in NSCLC compared to normal lung tissue (Jala et al 2012), and higher expression correlated with poor postoperative prognosis in NSCLC patients (Li et al 2022). Studies have indicated that the activation of EGFR via GPER1 leads to the phosphorylation of ERK1/2, which promotes the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9).…”

Section: Introductionmentioning

confidence: 99%

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis

Chen,

Zhao,

Wang

et al. 2024

Mol Med

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Background Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. Methods The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. Results GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. Conclusion GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects. Graphical Abstract

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Cytoplasmic expression of G protein-coupled estrogen receptor 1 correlates with poor postoperative prognosis in non-small cell lung cancer

Cited by 6 publications

References 45 publications

Multi-omics identification of GPCR gene features in lung adenocarcinoma based on multiple machine learning combinations

Multi-omics identification of GPCR gene features in lung adenocarcinoma based on multiple machine learning combinations

The G Protein-Coupled Estrogen Receptor GPER in the Development and Progression of Cancer

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis

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