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 <600 pg/ml. ANOS1 may represent a biomarker for GC phenotypes and as a target for therapy.Although declining gradually in prevalence, gastric cancer (GC) is the fourth most common malignancy and the second leading cause of cancer-related death worldwide. 1,2 Despite improvements in surgical techniques and chemotherapy, GC still represents a global public health problem with a 5-year overall survival of <25%. 3,4 Uncovering the molecular and cellular mechanisms involved in GC pathogenesis is pivotal to the development of more sensitive and specific biomarkers as well as enhanced molecular-targeting treatments that are required to overcome this devastating disease.GC is a phenotypically and genetically heterogeneous disease. [5][6][7] The main histological variants of GC are the intestinal type with clearly defined glandular structures and the diffuse type characterized by infiltrating neoplastic cells. 3 GC is etiologically associated with the combined effects of environmental factors and patients with predisposing genetic variants. 8,9 Moreover, the accumulation of genetic and epigenetic alterations contributes to the selection of neoplastic clones in a preferred tumor microenvironment. 6,10 The complicated molecular pathogenesis of GC caused by tumor heterogeneity makes it difficult to identify diagnostic and therapeutic targets that are useful for the management of patients. 7,11,12 A system for stratifying patients with GC according to genotype was proposed that facilitates the discovery of genes that contribute to the pathogenesis of GC.The Anosmin-1 (ANOS1) gene encodes cell adhesion protein that is a component of the extracellular matrix (ECM). 13 ANOS1...

Esophageal squamous cell carcinoma (ESCC), the most common esophageal cancer in East Asia, is among the six cancers with the highest fatality rates worldwide. Unfortunately, multidisciplinary treatment strategies have not achieved satisfactory outcomes. Therefore, novel insights into the molecular biology of ESCC are required to improve treatment. The gene encoding the transmembrane adherens junctions-associated protein-1 (AJAP1) expressed by epithelial cells resides in chromosome 1p36, which is frequently lost or epigenetically silenced in several malignancies. Here, we investigated the expression levels and regulatory mechanism of AJAP1 transcription. We determined the levels of AJAP1 mRNA and the genes encoding potentially interacting proteins expressed by ESCC cell lines, as well as the chromosomal copy number of AJAP1 and the methylation status of its promoter region. AJAP1 mRNA levels of 78 pairs of surgically resected specimens were determined to evaluate the association of AJAP1 expression and clinicopathological factors. Nine ESCC cell lines differentially expressed AJAP1 mRNA, and demethylation of hypermethylated AJAP1 genomic DNA reactivated AJAP1 mRNA expression. The copy number of sequences upstream or downstream of the AJAP1 transcriptional start site was not detectably altered. AJAP1 mRNA levels correlated inversely with those of ezrin (EZR) and were significantly lower in ESCC tissues compared with adjacent normal tissues. AJAP1 mRNA levels decreased gradually with increasing tumor stage. Patients with downregulated AJAP1 transcription were more likely to experience shorter overall and disease-free survival. Multivariate analysis of disease-free survival identified downregulated AJAP1 transcription as an independent prognostic factor. These results suggest that in ESCC, AJAP1 acts as a putative tumor suppressor and that AJAP1 transcription is regulated by promoter hypermethylation. These findings indicate that downregulated AJAP1 transcription may serve as a novel tumor biomarker to predict recurrence of ESCC after esophagectomy.

AJAP1 may function as a key regulatory molecule associated with the recurrence of HCC. Hypermethylation of the AJAP1 promoter is a key regulatory mechanism controlling AJAP1 expression.

Our findings indicate that inhibition of SAMSN1 transcription through DNA hypermethylation may influence the progression of HCC and thus represent a novel biomarker of the phenotype of HCC cells.

Abstract.The prognosis for patients with advanced gastric cancer (GC) remains poor. The identification of biomarkers relevant to the recurrence and metastasis of GC is advantageous for stratifying patients and proposing novel molecular targets. In the present study the oncological roles of SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1), a mediator of B-cell function, were elucidated in GC. The expression and methylation status of SAMSN1 were investigated in a panel of 11 GC cell lines. Immunohistochemical staining was performed to determine the pattern of SAMSN1 protein expression in gastric tissues. The prognostic impact of SAMSN1 expression was determined by analyzing 175 pairs of surgically resected gastric tissues. A marked decrease in the level of SAMSN1 mRNA was detected in 8/11 GC cell lines as compared with that in a non-transformed intestinal epithelium cell line (FHs 74) without promoter methylation. The mean expression level of SAMSN1 mRNA was reduced in GC tissues compared with normal adjacent tissues, an observation that was independent of tumor differentiation. The pattern of SAMSN1 protein expression was significantly correlated with that of SAMSN1 mRNA. Low SAMSN1 mRNA expression was significantly associated with tumor size (>60 mm; P=0.026) and shorter overall survival times (P=0.004). Multivariate analysis identified low SAMSN1 mRNA expression as an independent prognostic factor for poor overall survival (hazard ratio, 1.80; 95% confidence interval, 1.07-3.05; P= 0.025). The difference in survival between the low and high SAMSN1 expression groups was more marked in patients with stage II/III GC compared to those with stage IV GC. In patients with stage II/III GC who underwent curative surgery, low SAMSN1 expression was associated with reduced disease free survival times. The results of the present study indicate that downregulation of SAMSN1 transcription may affect the progression and recurrence of GC, and therefore may represent a novel biomarker of GC.