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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

Down regulation of neogenin inhibited cell growth and invasionA. The expression of Ntn4 receptors, neogenin (Neo), DCC and UNC5A-D were detected by Q-PCR. B. Neo expression was detected in the cells by western blot at 48 hours after transfected with siNeo or siControl. C. Neo silencing suppressed cell proliferation. Cells were transfected with siNeo or siControl for 48 hours and subjected to CCK8 assay. D. Neo knockdown restrained cell invasion. Cells were transfected with siNeo or siControl for 48 hours and subjected to the invasion assay; Magnification, × 100. Mean ± SEM, n ≥ 3. *p < 0.05, **p < 0.01, ***p < 0.001.
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Figure 4: Down regulation of neogenin inhibited cell growth and invasionA. The expression of Ntn4 receptors, neogenin (Neo), DCC and UNC5A-D were detected by Q-PCR. B. Neo expression was detected in the cells by western blot at 48 hours after transfected with siNeo or siControl. C. Neo silencing suppressed cell proliferation. Cells were transfected with siNeo or siControl for 48 hours and subjected to CCK8 assay. D. Neo knockdown restrained cell invasion. Cells were transfected with siNeo or siControl for 48 hours and subjected to the invasion assay; Magnification, × 100. Mean ± SEM, n ≥ 3. *p < 0.05, **p < 0.01, ***p < 0.001.

Mentions: Ntn4 is a secretory protein and exerts its effects by binding to its receptor on cell membrane. To identify which receptors that mediate the biologic functions of Ntn4 in GC cells, we first determined the expression of the known receptors of Ntn family including Neo, DCC and UNC5A-D in the AGS and MGC803 cells by Real-time PCR, and found that Neo is the highest expressed receptor of Ntn4 in these two GC cells (Fig. 4A). Therefore, we hypothesized that Neo may be invovled in Ntn4 induced cell proliferation and motility changes.


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)

Down regulation of neogenin inhibited cell growth and invasionA. The expression of Ntn4 receptors, neogenin (Neo), DCC and UNC5A-D were detected by Q-PCR. B. Neo expression was detected in the cells by western blot at 48 hours after transfected with siNeo or siControl. C. Neo silencing suppressed cell proliferation. Cells were transfected with siNeo or siControl for 48 hours and subjected to CCK8 assay. D. Neo knockdown restrained cell invasion. Cells were transfected with siNeo or siControl for 48 hours and subjected to the invasion assay; Magnification, × 100. Mean ± SEM, n ≥ 3. *p < 0.05, **p < 0.01, ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Down regulation of neogenin inhibited cell growth and invasionA. The expression of Ntn4 receptors, neogenin (Neo), DCC and UNC5A-D were detected by Q-PCR. B. Neo expression was detected in the cells by western blot at 48 hours after transfected with siNeo or siControl. C. Neo silencing suppressed cell proliferation. Cells were transfected with siNeo or siControl for 48 hours and subjected to CCK8 assay. D. Neo knockdown restrained cell invasion. Cells were transfected with siNeo or siControl for 48 hours and subjected to the invasion assay; Magnification, × 100. Mean ± SEM, n ≥ 3. *p < 0.05, **p < 0.01, ***p < 0.001.
Mentions: Ntn4 is a secretory protein and exerts its effects by binding to its receptor on cell membrane. To identify which receptors that mediate the biologic functions of Ntn4 in GC cells, we first determined the expression of the known receptors of Ntn family including Neo, DCC and UNC5A-D in the AGS and MGC803 cells by Real-time PCR, and found that Neo is the highest expressed receptor of Ntn4 in these two GC cells (Fig. 4A). Therefore, we hypothesized that Neo may be invovled in Ntn4 induced cell proliferation and motility changes.

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