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

Lv B, Song C, Wu L, Zhang Q, Hou D, Chen P, Yu S, Wang Z, Chu Y, Zhang J, Yang D, Liu J - Oncotarget (2015)

Bottom Line: However, it is completely unknown whether Ntn4 has roles in GC development.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of Ntn4 or Neo on JAK/Stat, PI3K/Akt, ERK/MAPK signalingA–B. Ntn4 silencing down-regulated the expression of MMP2 (A) and up-regulated the expression of TIMP1 (B). Cells were transfected with siRNAs for 48 hours and subjected to western blot with indicated antibodies. C. Neo ablation down-regulated MMP2 and up-regulated TIMP1. D–E. Effect of Ntn4 knockdown (D) and Ntn4 overexpression (E) on phosphorylation of Stat3, Akt, ERk and p38. The phosphorylation level was evaluated by western blot with specific antibodies to p-Stat3, p-Akt, p-ERK and p-p38, respectively. F. Effect of Neo knockdown on p-Stat3, p-Akt, p-ERK and p-p38.
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Figure 6: Effects of Ntn4 or Neo on JAK/Stat, PI3K/Akt, ERK/MAPK signalingA–B. Ntn4 silencing down-regulated the expression of MMP2 (A) and up-regulated the expression of TIMP1 (B). Cells were transfected with siRNAs for 48 hours and subjected to western blot with indicated antibodies. C. Neo ablation down-regulated MMP2 and up-regulated TIMP1. D–E. Effect of Ntn4 knockdown (D) and Ntn4 overexpression (E) on phosphorylation of Stat3, Akt, ERk and p38. The phosphorylation level was evaluated by western blot with specific antibodies to p-Stat3, p-Akt, p-ERK and p-p38, respectively. F. Effect of Neo knockdown on p-Stat3, p-Akt, p-ERK and p-p38.

Mentions: In order to further understand how Ntn4 induced the cell invasion, we examined the expression of two invasion-related biomarkers, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 1 (TIMP1). As shown in Fig. 6A and 6C, when blocking the Ntn4-Neo complex through interfering either Ntn4 or Neo, we observed the expression of MMP2 was significantly downregulated, meanwhile TIMP1 was upregulated as compared with control. Conversely, overexpression of Ntn4 increased MMP2 level and decreased TIMP1 level, implying that Ntn4 could enhance invasion of GC cells by leading to an imbalance between MMP2 and TIMP1 (Fig. 6B).


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

Lv B, Song C, Wu L, Zhang Q, Hou D, Chen P, Yu S, Wang Z, Chu Y, Zhang J, Yang D, Liu J - Oncotarget (2015)

Effects of Ntn4 or Neo on JAK/Stat, PI3K/Akt, ERK/MAPK signalingA–B. Ntn4 silencing down-regulated the expression of MMP2 (A) and up-regulated the expression of TIMP1 (B). Cells were transfected with siRNAs for 48 hours and subjected to western blot with indicated antibodies. C. Neo ablation down-regulated MMP2 and up-regulated TIMP1. D–E. Effect of Ntn4 knockdown (D) and Ntn4 overexpression (E) on phosphorylation of Stat3, Akt, ERk and p38. The phosphorylation level was evaluated by western blot with specific antibodies to p-Stat3, p-Akt, p-ERK and p-p38, respectively. F. Effect of Neo knockdown on p-Stat3, p-Akt, p-ERK and p-p38.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496398&req=5

Figure 6: Effects of Ntn4 or Neo on JAK/Stat, PI3K/Akt, ERK/MAPK signalingA–B. Ntn4 silencing down-regulated the expression of MMP2 (A) and up-regulated the expression of TIMP1 (B). Cells were transfected with siRNAs for 48 hours and subjected to western blot with indicated antibodies. C. Neo ablation down-regulated MMP2 and up-regulated TIMP1. D–E. Effect of Ntn4 knockdown (D) and Ntn4 overexpression (E) on phosphorylation of Stat3, Akt, ERk and p38. The phosphorylation level was evaluated by western blot with specific antibodies to p-Stat3, p-Akt, p-ERK and p-p38, respectively. F. Effect of Neo knockdown on p-Stat3, p-Akt, p-ERK and p-p38.
Mentions: In order to further understand how Ntn4 induced the cell invasion, we examined the expression of two invasion-related biomarkers, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 1 (TIMP1). As shown in Fig. 6A and 6C, when blocking the Ntn4-Neo complex through interfering either Ntn4 or Neo, we observed the expression of MMP2 was significantly downregulated, meanwhile TIMP1 was upregulated as compared with control. Conversely, overexpression of Ntn4 increased MMP2 level and decreased TIMP1 level, implying that Ntn4 could enhance invasion of GC cells by leading to an imbalance between MMP2 and TIMP1 (Fig. 6B).

Bottom Line: However, it is completely unknown whether Ntn4 has roles in GC development.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus