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Liver metastasis is often fatal in patients with gastric cancer, therefore, we aimed to identify genes associated with the mechanisms of liver metastasis of gastric cancer (GC) and to investigate their potential to predict recurrence and to serve as targets of therapy. Recurrence pattern-specific transcriptome analysis was performed to identify liver metastasis-associated genes. A stable knockout cell line was generated to investigate metabolic pathways that contribute to the malignant phenotype in vitro and vivo. Three hundred GC patients were analyzed to demonstrate an association between gene expression levels and clinicopathological parameters. As a results extracellular matrix complex subunit 1 (FRAS1) was identified as a liver metastasis-associated gene. Pathway analysis revealed that FRAS1 expression was significantly correlated with the expression of genes encoding TGFB1, MAP1B, AHNAK, BMP2, MUC1, BIRC5, MET, CDH1, RB1 and MKI67. FRAS1 expression was associated with the activation of the EGFR and PI3K signaling pathways. The proliferation ability of FRAS1 knockout cell line (FRAS1-KO) was inhibited compared to that of the parent cell line through caspase activity increment and cell cycle alteration. FRAS1-KO cells exhibited increased responsiveness to oxygen stress and diminished stemness, invasiveness, and migration. Mouse models of GC revealed decreases in tumor formation and generation of metastasis by FRAS1-KO cells. Moreover, the cumulative liver recurrence rate was significantly increased in patients with GC with high FRAS1 expression levels. We concluded that FRAS1 contributes to the malignant phenotype of GC, especially liver metastasis, and may therefore serve as a predictive marker or a target for treating liver metastasis.

Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection.

Gastric cancer (GC) is a major global health problem that urgently requires novel molecular biomarkers for patient stratification as well as therapeutic targets. Anosmin-1 (ANOS1) gene encodes a cell adhesion molecule that plays diverse roles in multiple malignancies. We performed global expression profiling of GC cell lines and small interfering RNA (siRNA) experiments to determine the effect of ANOS1 expression on phenotype. We evaluated the association of ANOS1 mRNA and protein levels in patients' tissue and sera with clinicopathological factors of GC subtypes. Differential expression of ANOS1 mRNA by GC cell lines correlated positively to levels of ITGAV, FOXC2 and NODAL mRNAs and inversely with those of TFPI2. Inhibiting ANOS1 expression decreased the proliferation, invasion and migration of GC cells. The mean level of ANOS1 mRNA was significantly higher in 237 GC tissues compared with the corresponding noncancerous adjacent tissues. Elevated ANOS1 levels associated significantly with the phenotypes of GC, shorter disease-free and overall survival. ANOS1 expression was a more significant prognostic marker for diffuse and distal nondiffuse GC. ANOS1 concentrations in sera increased sequentially in sera of healthy subjects, localized GC and disseminated GCs. Prognosis was worse for patients with preoperative serum ANOS1 ≥ 600 pg/ml compared with those with