Adherens junctions associated protein 1 serves as a predictor of recurrence of squamous cell carcinoma of the esophagus

Abstract

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.

Endogenous AJAP1 associates with the cytoskeleton and attenuates angiogenesis in endothelial cells

“…It has been shown that the expression of AJAP1 is dysregulated in various cancer types including glioma (Lin et al, 2012; McDonald et al, 2006), hepatocellular carcinoma (HCC) (Ezaka et al, 2015) and esophageal squamous cell carcinoma (ESCC) (Tanaka et al, 2015). …”

Genome-Wide Association Studies and Epigenome-Wide Association Studies Go Together in Cancer Control

“…The 'integrome' proposed by these authors represents integration of pathways, methylation status and gene expression in esophageal cancer. Other investigators identified epigenetic regulation of the transmembrane AJAP-1 and its association with recurrence of esophageal cancer [52].…”

“…DNA methylation is a potential tumor marker for several cancers because of its heritable and stable characteristics [109]. DNA methylation at specific loci reflects the characteristic clinicopathological features [52]. Genome-wide analysis of DNA methylation has revealed that epigenetic regulation is not only a site-specific event but also spans long stretches of chromosome regions consisting of clusters of contiguous CpG islands [110,111].…”

“…Genome-wide methylation [52]; the major genes affected were PTK2, RND1, and UBL3 which regulate recurrence of cancer [52] Sensitive locus for mutations 4q21 [22] 4q21 [22] SNP rs1229984 in ADH1B [22] SNP rs7922612 related with survival [22] Germline copy number loss of UGT28 and gain of PLEC [53] Gastric cancer FAT4, a novel tumor suppressor identified by exome sequencing gets inactivated due to hypermethylation (field canerization) [54] Epigenetic silencing of GLDC [57] Susceptibility locus 8q24 [55] 8q24.3 [58] SNP rs4733616 [55] SNP rs2294008 was associated with decreased risk of duodenal cancer [55] SNP rs2294008 was found to be associated with increased risk of gastric cancer and decreased risk of duodenal cancer [58] SNP rs2976392 [22] Loss of CNV at 5q22 region surrounding APC [56] Hepatocellular carcinoma (liver cancer)…”

Identification of NCCRP1 as an epigenetically regulated tumor suppressor and biomarker for malignant phenotypes of squamous cell carcinoma of the esophagus

“…Esophageal squamous cell carcinoma (ESCC) is a dominant histological type of esophageal malignances (3,4). The poor prognosis and increasing incidence of ESCC highlight the need for improved detection, prediction, monitoring, and treatment methods (2,5).…”