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.
Highlights
Gastric cancer (GC) is one of the most common malignancies worldwide, accounting for 8% of the total cases and 10% of total deaths [1]
Our results demonstrated that siNtn4 inhibited cell proliferation of the GC cells
Fewer cells treated with siNeo passed through the matrigel than that with siConrol (Fig. 4D, left panel), with the number of AGS 87/118 and of MGC803 187/269 (Fig. 4D, right panel). These findings showed that silence of Ntn4 receptor, Neo could result in the cell proliferation arrest and reduction of the cell invasion in both GC cell lines, which suggested the effect of Ntn4 on cell proliferation and motility may be mediated through its receptor, Neo
Summary
Gastric cancer (GC) is one of the most common malignancies worldwide, accounting for 8% of the total cases and 10% of total deaths [1]. Surgical resection remains the first choice for treating GC, it is always unavailable for a majority of patients due to a delayed diagnosis [2], which is mostly caused by a lack of efficient non-invasive test. Netrins are a conserved family of laminin-like secreted proteins that were originally identified as axonal guidance molecules [4]. Netrin system is composed of at least five ligands (netrin 1, 3, 4, G1a, and G1b) and seven potential receptors [deleted in colorectal cancer (DCC), neogenin (Neo), uncoordinated family member 5 (UNC5A-D) and the adenosine A2b receptor (A2b)] [14, 15]
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