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

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.

SUBMITTER: Lv B

PROVIDER: S-EPMC4496398 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Lv Bin B Song Chunhua C Wu Lijun L Zhang Qi Q Hou Daisen D Chen Ping P Yu Shunji S Wang Zhicheng Z Chu Yiwei Y Zhang Jun J Yang Dongqin D Liu Jie J

Oncotarget 20150101 12

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 additio ...[more]

PMID: 25909166

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Project description:Background: Actin-related protein 2/3 complex subunit 2 (ARPC2) plays a fundamental role in actin filament nucleation and is critical for tumor cell migration and invasion. However, its abnormal expression, clinical significance, and biological function in human pan-cancer have been poorly explored. Thus, we focused on ARPC2 as an entry point for identifying novel pan-cancer prognostic biomarkers. Methods: The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were used to assess the differential expression of ARPC2 in pan-cancer. The Human Protein Atlas was used for the tissue/cell-specific expression analysis of ARPC2. The genetic alteration information of ARPC2 was obtained from the cBioPortal database and the GSCALite platform. The prognostic value of ARPC2 was explored in pan-cancer using Cox regression and Kaplan–Meier analyses. Spearman correlation analysis was performed to investigate the relationship between ARPC2 expression and tumor mutational burden (TMB), DNA methyltransferases, microsatellite instability (MSI), immune-related genes, and mismatch repairs (MMRs). The ESTIMATE and CIBERSORT algorithms were used to evaluate the association between ARPC2 expression and the tumor microenvironment (TME) and immune infiltrating cells. We also conducted differential expression analysis of ARPC2 in hepatocellular carcinoma (HCC) tissues and cell lines using qPCR, western blotting, and immunohistochemistry and explored its role in tumor proliferation, migration, and invasion of HCC cells. Results: ARPC2 expression was significantly upregulated in multiple tumor types and significantly correlated with worse prognosis and higher clinicopathological stage. Genetic alterations and DNA methylation in tumor tissues may contribute to the aberrant expression of ARPC2. ARPC2 expression was significantly correlated with the tumor microenvironment (TME), infiltrating immune cells, TMB, microsatellite instability (MSI), and immune checkpoint-related genes in certain cancer types. In this experimental study, we found that the expression of ARPC2 was dramatically upregulated in HCC tissues and cell lines compared to adjacent liver tissues and normal liver cell lines. Functionally, ARPC2 silencing in HCC cells significantly inhibited cell proliferation, migration, and invasion, while the overexpression of ARPC2 promotes tumor proliferation, migration, and invasion. Conclusion: ARPC2 is a promising prognostic and immunological biomarker for multiple tumor types and is likely to play an important role in HCC progression and metastasis.

Dataset Information

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

Publications

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

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