MicroRNA-200 family members and ZEB2 are associated with brain metastasis in gastric adenocarcinoma

Abstract

Abstract. Although the incidence of brain metastasis in gastric cancer is relatively low, its prevalence may increase with improved therapy and longer survival tumors. The molecular mechanisms underlying brain metastases are not well understood. To gain insight into the mechanism of brain metastasis, we studied differences in microRNA (miRNA) expression levels in 8 cases of matched primary gastric adenocarcinoma and brain metastatic adenocarcinoma using the Illumina microRNA microarray chip. We identified 6 upregulated and 2 downregulated miRNAs in all 8 cases simultaneously. Interestingly, 2 out of 8 miRNAs (hsa-miR-141-3p and hsa-miR-200b-3p) belonged to the miR-200 family. Online microRNA database searching revealed that ZEB2 is the topranked target gene for hsa-miR141-3p and hsa-miR-200b-3p, prompting us to focus ZEB2 expression in brain metastatic adenocarcinoma. We confirmed that ZEB2 expression was markedly downregulated in some brain metastatic samples. In addition, decreased ZEB2 expression was noted by western blot analysis of 2 metastatic gastric adenocarcinoma cell types that were derived by in vivo selection following intracardiac injection of gastric cancer cell lines. In conclusion, we demonstrate that expression of miRNA-200 family members and ZEB2 are associated with brain metastases of gastric adenocarcinoma, not only in matched patient samples, but also in metastatic cell lines that were derived by in vivo selection. IntroductionAlthough the incidence of gastric cancer has been declining since 1950, gastric cancer remains the 4th most common cancer worldwide (1). The prevalence of gastric cancer shows wide geographic variations, with the highest rates found in Eastern Asia (including China, Japan and Korea), Eastern Europe, and Central and Latin America (1). In a recent report by the World Health Organization, gastric cancer was classified into 5 main types of adenocarcinomas and rare variants (2). In contrast to the better prognoses associated with early gastric cancers, advanced gastric cancers generally have poor prognoses, with known prognostic factors including stage and the number of lymph node metastases (2). Unlike lung or breast cancer, the brain metastases of gastric cancer are very rare and have been reported in <1% of clinical cases (3,4), most cases of which were reported as leptomeningeal carcinomatosis (5-7).Prolonged survival in gastric cancer patients accompanying improvements in systematic approaches and overall patient care has increased the likelihood of patients developing central nervous system metastases (8). Similarly, the incidence of brain metastasis in non-small cell lung cancer patients has increased in recent years (9), likely resulting from improved therapy, diagnostic modalities, and screening programs for early detection. In addition, evidence suggests that improved targeted therapy in patients with HER-2-positive breast cancer may increase the incidence of brain metastases (10,11). Although there is no established targeted therapy for treating gastric cancer,...

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

“…Loss of E-cadherin is generally accepted to be a hallmark event of the EMT process, during which epithelial cells undergo profound phenotypic modification and lack of polarity to turn into mesenchymal cells, reducing contact with surrounding cells or matrix as well as acquiring the ability of migration and invasion. of brain metastasis or small sample size due to low incidence (39). However, this finding might support the theory of MET process that anchors circulating cancer cells to metastatic organs, although the effect of this in metastatic dissemination is still under debate (40).…”

MicroRNAs Associated with Epithelial-Mesenchymal Transition Can Be Targeted to Inhibit Peritoneal Dissemination of Human Scirrhous Gastric Cancers

“…According to recent studies [39-41], ZEB1 plays a valuable role and has clinical significance in peritoneal dissemination of gastric cancers, and is a promising target molecule for prognosis and therapy. More recently, ZEB2 has been garnering similar attention for its potential in gastric [42, 43] and other cancers [44, 45]. Indeed, we found that siRNA-mediated downregulation of ZEB1 or ZEB2 successfully inhibited peritoneal dissemination in our own orthotopic 58As9 tumor models (Takei Y, et al, unpublished results).…”

Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features

“…Investigations of miRNAs as biomarkers have employed the expression profiling of non-invasive samples such as body fluids [3].Various studies on epithelial malignancies have shown encouraging results on various fronts [4]. Aberrant expression of the miR-200 family has been linked to the occurrence and development of various types of malignant tumors [5] including hepatocellular carcinoma [6], colon cancer [7],breast cancer [8], ovarian cancer [9], lung cancer [10], gastric cancer [11,12], osteosarcoma [13], etc. Although miR-200 family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive [14].…”