GAP43, a novel metastasis promoter in non-small cell lung cancer

被引:18
|
作者
Zhang, Fanrong [1 ,2 ,3 ]
Ying, Lisha [2 ,3 ]
Jin, Jiaoyue [2 ,3 ,4 ]
Feng, Jianguo [2 ,3 ]
Chen, Kaiyan [2 ,3 ]
Huang, Minran [2 ,3 ]
Wu, Yingxue [2 ,3 ]
Yu, Herbert [5 ]
Su, Dan [2 ,3 ,4 ]
机构
[1] Zhejiang Canc Hosp, Dept Breast Surg, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Canc Hosp, Canc Res Inst, 1 East Banshan Rd, Hangzhou 310022, Zhejiang, Peoples R China
[3] Key Lab Diag & Treatment Technol Thorac Oncol Zhe, 1 East Banshan Rd, Hangzhou 310022, Zhejiang, Peoples R China
[4] Zhejiang Canc Hosp, Dept Pathol, Hangzhou, Zhejiang, Peoples R China
[5] Univ Hawaii, Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96822 USA
来源
JOURNAL OF TRANSLATIONAL MEDICINE | 2018年 / 16卷
基金
中国国家自然科学基金;
关键词
Non-small cell lung cancer; Metastasis; High-throughput assays; GAP43; F-actin; TRANSCRIPTION FACTOR SNAIL; BRAIN METASTASIS; BREAST-CANCER; GENE-EXPRESSION; SERINE; 41; CARCINOMA; GAP-43; PROGNOSIS; INVASION; DISEASE;
D O I
10.1186/s12967-018-1682-5
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 3years 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.
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页数:12
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