The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression

Abstract

Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (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. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-β signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-β in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-β signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.

The Roles of MicroRNA-141 in Human Cancers: From Diagnosis to Treatment

“…Overexpression of miR-141 suppressed tumor growth and pulmonary metastasis in nude mice. In clinical samples, the expression of miR-141 was inversely correlated with TNM stage, tumor invasion depth, tumor embolus and disease-free survival [40]. Further study indicated that the miR-200c and miR-141 cluster (miR-200c/141) could inhibit migration and invasion of gastric cancer by directly targeting of ZEB1 and ZEB2 and the subsequent restoration of E-cadherin [100].…”

“…Furthermore, DNA methylation maintains the balance of tissue-specific expression of the miR-200c/141 cluster in normal cells and affects the phenotypic changes observed in cancer cells. Current findings indicate that downregulation of miR-200c and miR-141 is due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated transforming growth factor (TGF)-β signaling [40]. The double-negative feedback loop controlling ZEB1 is perhaps the best known mechanism of miR-200c/141 action.…”

Demethylation drug 5-Aza-2′-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro

“…Deregulation of miR-200c has been identified to be associated with various types of human cancer, including ovarian, breast, prostate, gastric and bladder cancer (10)(11)(12)(13)(14). miR-200c has been identified as being frequently downregulated in ccRCC (15).…”

miR-141-3p Suppresses Expression of Androgen Receptors and Functions as a Tumor Suppressor Gene in Prostate Carcinogenesis

“…Using deep-sequencing analysis, we found that miR-141-3p expression was decreased by 1.26-fold in early PCa compared to that in BPH (P < 0.05), and confirmed a similar 1.17-fold decrease in early PCa compared to that in BPH (P = 0.2053) by qRT-PCR. In addition, miR-141-3p expression levels vary in different tumors, with overexpression observed in bladder [16], urothelial [17], breast [18] [19], ovarian [20], endometrioid [21], cholangiocytes [22] and colorectal cancers [23] and NSCLC [24], while expression is downregulated in gastric cancer [25], hepatocellular carcinomas [26] [27], renal cell carcinoma [28], lymphatic metastatic pancreatic cancer [29], pituitary tumors [30], craniopharyngioma [31], head and neck cancer [32], osteosarcoma [33], and cutaneous T cell lymphoma [34]. These reports provide compelling evidence for a role of miR-141-3p as an oncogene or tumor suppressor in different tumors and at different stages.…”