Abstract
BackgroundBrain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC.MethodsWe performed high-throughput Luminex assays to profile the transcriptional levels of 36 genes in 70 operable NSCLC patients, among whom 37 developed brain metastases as the first relapse within 3 years after surgery. The Cox proportional hazards regression model was used to evaluate the association between genes and brain metastases. Wound healing assay and transwell assay was carried out to estimate the function of target gene in vitro. And left ventricular injection on nude mice was used to evaluate the effect of target gene in vivo.ResultsGrowth-associated protein 43 (GAP43) was found to be related to brain metastasis. Multivariate Cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.29-fold increase in the risk for brain metastasis compared with those with low levels (95% confidence interval: 1.55–7.00; P = 0.002). Kaplan–Meier survival curves revealed that GAP43 was also associated with overall survival. Analysis of a cohort of 1926 NSCLC patients showed similar results: patients with high levels of GAP43 had worse progression-free and overall survival rates. Furthermore, in vitro experiments showed that GAP43 facilitated cell migration. Animal studies demonstrated that GAP43-silenced NSCLC cells were less likely to metastasize to the brain and bone than control cells. Immunofluorescence and F-actin/G-actin in vivo assays indicated that GAP43 knockdown triggered depolymerization of the F-actin cytoskeleton. Rho GTPase activation assays showed that Rac1 was deactivated after GAP43 was silenced.ConclusionsOur findings suggest that GAP43 is an independent predictor of NSCLC brain metastasis and that it may facilitate metastasis by regulating the Rac1/F-actin pathway.
Highlights
Brain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC)
Tumor cells arrested at the brain vascular branch can adhere to the endothelium and secrete certain cytokines, such as matrix metalloproteinases (MMPs), placental growth factor (PLGF) and vascular endothelial growth factor (VEGF), to break the tight junction and promote retraction of the endothelial monolayer [10,11,12]
In our previous retrospective study, we examined 637 operable NSCLC patients and developed a nomogram to predict the occurrence of brain metastases and identified high-risk NSCLC patients for prophylactic cranial irradiation treatment [17]
Summary
Brain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC. 20–30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases during the course of disease, and 10–20% of patients present with a synchronous diagnosis of brain metastases and a primary tumor [1, 2]. A successful brain metastatic cell requires specialized mechanisms to traverse the blood–brain barrier (BBB), a selective barrier. Zhang et al J Transl Med (2018) 16:310 formed by cerebrovascular endothelial cells that exerts the foremost control over the brain microenvironment [8, 9]. Much is still unknown about the exact mechanisms of brain metastasis, and little has been translated to clinical research and application
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