Research Papers:

Netrin-4 as a biomarker promotes cell proliferation and invasion in gastric cancer

Bin Lv, Chunhua Song, Lijun Wu, Qi Zhang, Daisen Hou, Ping Chen, Shunji Yu, Zhicheng Wang, Yiwei Chu, Jun Zhang, Dongqin Yang _ and Jie Liu

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Oncotarget. 2015; 6:9794-9806. https://doi.org/10.18632/oncotarget.3400

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Bin Lv1, Chunhua Song2, Lijun Wu1, Qi Zhang1,3, Daisen Hou1,3, Ping Chen1,3, Shunji Yu1,3, Zhicheng Wang4, Yiwei Chu5, Jun Zhang1, Dongqin Yang1, Jie Liu1

1Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China

2Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA

3Institutes of Biomedical Sciences of Shanghai Medical School, Fudan University, Shanghai, China

4Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai, China

5Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence to:

Dongqin Yang, e-mail: [email protected]

Jie Liu, e-mail: [email protected]

Keywords: netrin-4, gastric cancer, cell proliferation, cell motility

Received: January 20, 2015     Accepted: February 15, 2015     Published: March 18, 2015


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.

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