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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

Ntn4 was overexpressed in GCs and negatively correlated with patient survivalA. IHC staining of human GC tissues using Ntn4-specific antibody, as described in Methods; Magnification, × 200. B–C. Classification of samples according to the intensity of staining of Ntn4 expression (n = 82, p = 0.001). D. ELISA analysis to determine serum level of Ntn4 in GC patients and normal controls (n = 52, p < 0.001). E. Kaplan-Meier curves for GC patients' overall survival in the patients with high Ntn4 expression and low Ntn4 expression (n = 48, p = 0.038).
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Figure 7: Ntn4 was overexpressed in GCs and negatively correlated with patient survivalA. IHC staining of human GC tissues using Ntn4-specific antibody, as described in Methods; Magnification, × 200. B–C. Classification of samples according to the intensity of staining of Ntn4 expression (n = 82, p = 0.001). D. ELISA analysis to determine serum level of Ntn4 in GC patients and normal controls (n = 52, p < 0.001). E. Kaplan-Meier curves for GC patients' overall survival in the patients with high Ntn4 expression and low Ntn4 expression (n = 48, p = 0.038).

Mentions: As shown in Fig. 7A, Ntn4 expression was significantly higher in the tumor tissues (up panels) compared with adjacent tissues (down panels). Based upon the intensity of staining, we classified the samples into four groups with increasing staining intensity from weak (+) to the strongest (++++) (Fig. 7B). Its expression in majority of GC tissues was high, falling into group 3 and 4 and the expression in adjacent tissues was weak, falling into group 1 and 2 (Fig. 7C, p = 0.001). We further quantified the protein level of Ntn4 in GC patient's serum, as compared with normal population by ELISA analysis. As shown in Fig. 7D, the levels of Ntn4 in the sera of the tumor patients were significantly higher than those of the normal samples (n = 52, p < 0.0001).


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)

Ntn4 was overexpressed in GCs and negatively correlated with patient survivalA. IHC staining of human GC tissues using Ntn4-specific antibody, as described in Methods; Magnification, × 200. B–C. Classification of samples according to the intensity of staining of Ntn4 expression (n = 82, p = 0.001). D. ELISA analysis to determine serum level of Ntn4 in GC patients and normal controls (n = 52, p < 0.001). E. Kaplan-Meier curves for GC patients' overall survival in the patients with high Ntn4 expression and low Ntn4 expression (n = 48, p = 0.038).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Ntn4 was overexpressed in GCs and negatively correlated with patient survivalA. IHC staining of human GC tissues using Ntn4-specific antibody, as described in Methods; Magnification, × 200. B–C. Classification of samples according to the intensity of staining of Ntn4 expression (n = 82, p = 0.001). D. ELISA analysis to determine serum level of Ntn4 in GC patients and normal controls (n = 52, p < 0.001). E. Kaplan-Meier curves for GC patients' overall survival in the patients with high Ntn4 expression and low Ntn4 expression (n = 48, p = 0.038).
Mentions: As shown in Fig. 7A, Ntn4 expression was significantly higher in the tumor tissues (up panels) compared with adjacent tissues (down panels). Based upon the intensity of staining, we classified the samples into four groups with increasing staining intensity from weak (+) to the strongest (++++) (Fig. 7B). Its expression in majority of GC tissues was high, falling into group 3 and 4 and the expression in adjacent tissues was weak, falling into group 1 and 2 (Fig. 7C, p = 0.001). We further quantified the protein level of Ntn4 in GC patient's serum, as compared with normal population by ELISA analysis. As shown in Fig. 7D, the levels of Ntn4 in the sera of the tumor patients were significantly higher than those of the normal samples (n = 52, p < 0.0001).

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