title: Visfatin Mediates SCLC Cells Migration across Brain Endothelial Cells through Upregulation of CCL2.
abstract: Small-cell lung cancer (SCLC) is characterized as an aggressive tumor with brain metastasis. Although preventing SCLC metastasis to the brain is immensely important for survival, the molecular mechanisms of SCLC cells penetrating the blood-brain barrier (BBB) are largely unknown. Recently, visfatin has been considered as a novel pro-inflammatory adipocytokine involved in various cancers. Herein, we present evidence that elevated levels of visfatin in the serum of SCLC patients were associated with brain metastasis, and visfain was increased in NCI-H446 cells, a SCLC cell line, during interacting with human brain microvascular endothelial cells (HBMEC). Using in vitro BBB model, we found that visfatin could promote NCI-H446 cells migration across HBMEC monolayer, while the effect was inhibited by knockdown of visfatin. Furthermore, our findings indicated that CC chemokine ligand 2 (CCL2) was involved in visfatin-mediated NCI-H446 cells transendothelial migtation. Results also showed that the upregulation of CCL2 in the co-culture system was reversed by blockade of visfatin. In particular, visfatin-induced CCL2 was attenuated by specific inhibitor of PI3K/Akt signaling in NCI-H446 cells. Taken together, we demonstrated that visfatin was a prospective target for SCLC metastasis to brain, and understanding the molecular mediators would lead to effective strategies for inhibition of SCLC brain metastasis.
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. liutingting19881123@hotmail.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. zwmiao@mail.cmu.edu.cn.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. jjs19890504@hotmail.com.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. yuanshuai43210@126.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. fangwengang@126.com.
authors.forename: Wengang
authors.initials: W
authors.lastname: Fang
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. bli@mail.cmu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Lab of Cell Biology, Ministry of Public Health, Key Lab of Medical Cell Biology, Ministry of Education, Department of Developmental Biology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China. yhchen@mail.cmu.edu.cn.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D054409:Nicotinamide Phosphoribosyltransferase / Q000097:blood / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics*
chemical_list: D018932:Chemokine CCL2; D012333:RNA, Messenger; D054409:Nicotinamide Phosphoribosyltransferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: CC chemokine ligand 2 (CCL2); SCLC; blood–brain barrier (BBB); brain metastasis; transendothelial migration; visfatin