Abstract
Simple SummaryLung adenocarcinoma is one of the leading causes of cancer-related deaths. Even though advanced anticancer drugs are available, prognosis of patients with lung cancer is dismal and there is an urgent need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. GPR87 is upregulated in various cancers, but its biological function has not yet been established in lung cancer. Here, we discovered that GPR87 is upregulated in lung adenocarcinoma and overexpressed GPR87 contributes to poor prognosis in patients with lung adenocarcinoma. We used GPR87-overexpressing and GPR87-silenced lung adonocarcinoma cell lines, along with in vivo studies, to demonstrate that overexpression of GPR87 promoted invasiveness and metastasis of lung adenocarcinoma cells. Our study identified the AKT-eNOS-NO signaling axis to be the mechanism by which GPR87 exerted its oncogenic function.Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.
Highlights
Lung cancers are typically categorized into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)
We demonstrate that G protein-coupled receptor 87 (GPR87) is upregulated in lung adenocarcinoma and that overexpressed GPR87 contributes to a poor prognosis in lung adenocarcinoma patients
We show that upregulation of GPR87 in lung adenocarcinoma promoted metastatic properties both in vitro and in vivo through the activation of the AKT-eNOS-nitric oxide (NO) signaling pathway (Figure 6)
Summary
Lung cancers are typically categorized into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for more than 85% of lung cancers and is further subclassified into lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma [1]. Lung adenocarcinoma accounts for approximately ~80% of NSCLC cases [1]. Despite the development of advanced anticancer drugs to treat lung cancer, the prognosis of patients with lung cancer still remains poor [3,4]. Metastasis of the primary tumor to distant organs and resistance to therapeutic agents may be among several reasons for the poor prognosis associated with this subtype [5,6]. The identification of appropriate targets and elucidation of the oncogenic mechanisms underlying metastasis are critical for the development of novel therapeutic strategies for lung adenocarcinoma
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