title: Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer.
abstract: Gastric cancer (GC) is the second most common cause of cancer-related death with limited serum biomarkers for diagnosis and prognosis. Netrin-4 (Ntn4) is a laminin-related secreted molecule found to regulate tumor progression and metastasis. However, it is completely unknown whether Ntn4 has roles in GC development. Here, we first reported Ntn4 knockdown significantly suppressed cell proliferation and motility, while overexpression or addition of exogenous Ntn4 reversed these effects. In addition, Ntn4 receptor, neogenin (Neo) was also found highly expressed in GC cells and mediated the Ntn4-induced cell proliferation and invasion. Moreover, Ntn4 or Neo silencing decreased the phosphorylation of Stat3, ERK, Akt and p38, indicating multi-oncogenic pathways (Jak/Stat, PI3K/Akt, and ERK/MAPK) were involved in Ntn4-induced effects on the GC cells. Importantly, Ntn4 level was significantly increased in 82 tumor tissues (p = 0.001) and 52 serum samples (p < 0.0001) from GC patients and positively correlated with Neo expression (p = 0.003). Ntn4 expression was negatively correlated with the survival period (p = 0.038), and positively associated with the severity of pathological stages of the tumors (p = 0.008). Taken together, Ntn4 promoted the proliferation and motility of GC cells which was mediated by its receptor Neo and through further activation of multi-oncogenic pathways. Elevated Ntn4 was detected in both tumor tissues and serum samples of GC patients and suggested a relatively poor survival, indicating Ntn4 may be used as a potential non-invasive biomarker for diagnosis and prognosis of GC.
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.|Institutes of Biomedical Sciences of Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.|Institutes of Biomedical Sciences of Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Daisen
authors.initials: D
authors.lastname: Hou
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.|Institutes of Biomedical Sciences of Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.|Institutes of Biomedical Sciences of Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: Shunji
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Dongqin
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075385:Netrins; D010766:Phosphorylation; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism*; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; D034741:RNA, Small Interfering; C091279:neogenin
keywords: cell motility; cell proliferation; gastric cancer; netrin-4