ZEB2 Promotes the Metastasis of Gastric Cancer and Modulates Epithelial Mesenchymal Transition of Gastric Cancer Cells

Dai, Yinghuan; Tang, Yaping; Zhu, Hongyi; Lv, Liang; Chu, Yi-Min; Zhou, Yuqian; Huo, Jirong

doi:10.1007/s10620-012-2042-6

Cited by 56 publications

(54 citation statements)

References 28 publications

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“…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ZEB1 or ZEB2 successfully inhibited peritoneal dissemination in our own orthotopic 58As9 tumor models (Takei Y, et al, unpublished results).…”

Section: Discussionsupporting

confidence: 59%

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

et al. 2018

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Objectives: Scirrhous gastric cancers grow rapidly, and frequently invade the peritoneum. Such peritoneal dissemination properties markedly reduce patient survival. Thus, an effective means for inhibiting peritoneal dissemination is urgently required. Methods: We previously established a cell line, HSC-58, from a scirrhous gastric cancer patient, and further successfully isolated a metastatic line, 58As9, in nude mice upon orthotopic inoculation. Using the lines, we examined the mechanism underlying peritoneal dissemination from the viewpoint of microRNA (miRNA) expression. Results: miRNA array and qRT-PCR analysis showed that the expressions of epithelial-mesenchymal transition (EMT)-associated miRNAs such as miR-200c and miR-141 were significantly low in 58As9. Using 58As9 with stably overexpressing miR-200c, miR-141, or both, together with a luciferase reporter assay, we found that miR-200c targeted zinc finger E-box-binding homeobox 1 (ZEB1) and miR-141 targeted ZEB2. The overexpressed lines reversed the EMT status from mesenchymal to epithelial in 58As9, and significantly reduced the invasion activity and peritoneal dissemination for a significant prolongation of survival in the orthotopic tumor models in nude mice. Conclusions: EMT-associated miRNAs such as miR-200c and miR-141 and their target genes ZEB1/ZEB2 have good potential for antiperitoneal dissemination therapy in patients with scirrhous gastric cancers.

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Section: Discussionsupporting

confidence: 59%

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

et al. 2018

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“…Upregulation of ZEB2 mRNA is well demonstrated in various cancers. ZEB2 mRNA levels are generally correlated with tumor metastasis, differentiation grade and poor prognosis (28). From these results, we propose that ZEB2 may play an important role in the development of brain metastases of gastric adenocarcinoma via MET.…”

Section: Increased Mirna Ratiomentioning

confidence: 66%

“…The miR-200 family serves a critical role in the repression of E-cadherin by ZEB1/2 during EMT, thereby enhancing migration and invasion during cancer progression (18,19,25,26). It is well known that EMT and metastases are associated with E-cadherin and ZEB1/2 in gastric adenocarcinoma (20,27,28). Therefore, the upregulation of hsa-miR-141-3p and hsa-miR-200b-3p in the brain metastatic lesions may promote metastasis via mesenchymal-epithelial transition (MET) during the colonization of brain tissues.…”

Section: Increased Mirna Ratiomentioning

confidence: 99%

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

Minn

Lee

Hyung

et al. 2014

International Journal of Oncology

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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,...

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“…Many reports indicated that ZEB2 promotes induction of EMT in many human cancer cases (Imamichi et al, 2007;Maeda et al, 2005;Xia et al, 2010;Yoshihara et al, 2009), upregulation of MMP expression (Dai et al, 2012;Miyoshi et al, 2004), and promotion of metastasis (Dai et al, 2012). Research has demonstrated that the MMP9 activity is involved in tumor invasion and metastasis (Wang et al, 2008;Zhang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

ZEB2 promotes vasculogenic mimicry by TGF-β1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

Yang

Sun

et al. 2015

Experimental and Molecular Pathology

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ZEB2 Promotes the Metastasis of Gastric Cancer and Modulates Epithelial Mesenchymal Transition of Gastric Cancer Cells

Cited by 56 publications

References 28 publications

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

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

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

ZEB2 promotes vasculogenic mimicry by TGF-β1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma

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